Aminoheteroaryl compounds as protein kinase inhibitors

ABSTRACT

Aminopyridine and aminopyrazine compounds of formula (1), compositions including these compounds, and methods of their use are provided. Preferred compounds of formula 1 have activity as protein kinase inhibitors, including as inhibitors of c-MET

This application claims the benefit of U.S. Provisional Application Ser.No. 60/449,588, filed Feb. 26, 2003, and 60/540,229, filed Jan. 29,2004, the disclosures of which are hereby incorporated by reference intheir entireties.

FIELD OF THE INVENTION

The invention relates generally to novel chemical compounds and methods.More particularly, the invention provides novel aminoheteroarylcompounds, particularly aminopyridines and aminopyrazines, havingprotein tyrosine kinase activity, and methods of their synthesis anduse.

BACKGROUND

Protein kinases (“PKs”) are enzymes that catalyze the phosphorylation ofhydroxy groups on tyrosine, serine and threonine residues of proteins.The consequences of this seemingly simple activity are staggering; cellgrowth, differentiation and proliferation, i.e., virtually all aspectsof cell life in one way or another depend on PK activity. Furthermore,abnormal PK activity has been related to a host of disorders, rangingfrom relatively non-life threatening diseases such as psoriasis toextremely virulent diseases such as glioblastoma (brain cancer).

The PKs can be conveniently broken down into two classes, the proteintyrosine kinases (PTKs) and the serine-threonine kinases (STKs).

One of the prime aspects of PTK activity is their involvement withgrowth factor receptors. Growth factor receptors are cell-surfaceproteins. When bound by a growth factor ligand, growth factor receptorsare converted to an active form which interacts with proteins on theinner surface of a cell membrane. This leads to phosphorylation ontyrosine residues of the receptor and other proteins and to theformation inside the cell of complexes with a variety of cytoplasmicsignaling molecules that, in turn, effect numerous cellular responsessuch as cell division (proliferation), cell differentiation, cellgrowth, expression of metabolic effects to the extracellularmicroenvironment, etc. For a more complete discussion, see Schlessingerand Ullrich, Neuron 9:303–391 (1992), which is incorporated byreference, including any drawings, as if fully set forth herein.

Growth factor receptors with PTK activity are known as receptor tyrosinekinases (“RTKs”). They comprise a large family of transmembranereceptors with diverse biological activity. At present, at leastnineteen (19) distinct subfamilies of RTKs have been identified. Anexample of these is the subfamily designated the “HER” RTKs, whichinclude EGFR (epithelial growth factor receptor), HER2, HER3 and HER4.These RTKs consist of an extracellular glycosylated ligand bindingdomain, a transmembrane domain and an intracellular cytoplasmiccatalytic domain that can phosphorylate tyrosine residues on proteins.

Another RTK subfamily consists of insulin receptor (IR), insulin-likegrowth factor I receptor (IGF-1R) and insulin receptor related receptor(IRR). IR and IGF-1R interact with insulin, IGF-I and IGF-II to form aheterotetramer of two entirely extracellular glycosylated α subunits andtwo β subunits which cross the cell membrane and which contain thetyrosine kinase domain.

A third RTK subfamily is referred to as the platelet derived growthfactor receptor (“PDGFR”) group, which includes PDGFRα, PDGFRβ, CSFIR,c-kit and c-fms. These receptors consist of glycosylated extracellulardomains composed of variable numbers of immunoglobin-like loops and anintracellular domain wherein the tyrosine kinase domain is interruptedby unrelated amino acid sequences.

Another group which, because of its similarity to the PDGFR subfamily,is sometimes subsumed into the later group is the fetus liver kinase(“flk”) receptor subfamily. This group is believed to be made up ofkinase insert domain-receptor fetal liver kinase-1 (KDR/FLK-1), flk-1R,flk-4 and fms-like tyrosine kinase 1 (flt-1).

A further member of the tyrosine kinase growth factor receptor family isthe fibroblast growth factor (“FGF”) receptor subgroup. This groupconsists of four receptors, FGFR1–4, and seven ligands, FGF1–7. Whilenot yet well defined, it appears that the receptors consist of aglycosylated extracellular domain containing a variable number ofimmunoglobin-like loops and an intracellular domain in which thetyrosine kinase sequence is interrupted by regions of unrelated aminoacid sequences.

Still another member of the tyrosine kinase growth factor receptorfamily is the vascular endothelial growth factor (“VEGF”) receptorsubgroup. VEGF is a dimeric glycoprotein similar to PDGF but hasdifferent biological functions and target cell specificity in vivo. Inparticular, VEGF is presently thought to play an essential role isvasculogenesis and angiogenesis.

Still another member of the tyrosine kinase growth factor receptorfamily is MET, often referred to as c-Met, also known as humanhepatocyte growth factor receptor tyrosine kinase (hHGFR). c-Met isthought to play a role in primary tumor growth and metastasis.

A more complete listing of the known RTK subfamilies is described inPlowman et al., DN&P, 7(6):334–339 (1994), which is incorporated byreference.

In addition to the RTKs, there also exists a family of entirelyintracellular PTKs called “non-receptor tyrosine kinases” or “cellulartyrosine kinases.” This latter designation, abbreviated “CTK,” will beused herein. CTKs do not contain extracellular and transmembranedomains. At present, over 24 CTKs in 11 subfamilies (Src, Frk, Btk, Csk,Abl, Zap70, Fes, Fps, Fak, Jak and Ack) have been identified. The Srcsubfamily appear so far to be the largest group of CTKs and includesSrc, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1, AUR2 and Yrk. For a moredetailed discussion of CTKs, see Bolen, Oncogene, 8:2025–2031 (1993),which is incorporated by reference, including any drawings, as if fullyset forth herein.

The serine/threonine kinases, STKs, like the CTKs, are predominantlyintracellular although there are a few receptor kinases of the STK type.STKs are the most common of the cytosolic kinases; i.e., kinases thatperform their function in that part of the cytoplasm other than thecytoplasmic organelles and cytoskelton. The cytosol is the region withinthe cell where much of the cell's intermediary metabolic andbiosynthetic activity occurs; e.g., it is in the cytosol that proteinsare synthesized on ribosomes. The STKs include CDk2, Raf, the ZC familyof kinases, the NEK family of kinases, and BUB1.

RTKs, CTKs and STKs have all been implicated in a host of pathogenicconditions including, significantly, cancer. Other pathogenic conditionswhich have been associated with PTKs include, without limitation,psoriasis, hepatic cirrhosis, diabetes, angiogenesis, restenosis, oculardiseases, rheumatoid arthritis and other inflammatory disorders,immunological disorders such as autoimmune disease, cardiovasculardisease such as atherosclerosis and a variety of renal disorders.

With regard to cancer, two of the major hypotheses advanced to explainthe excessive cellular proliferation that drives tumor developmentrelate to functions known to be PK regulated. That is, it has beensuggested that malignant cell growth results from a breakdown in themechanisms that control cell division and/or differentiation. It hasbeen shown that the protein products of a number of proto-oncogenes areinvolved in the signal transduction pathways that regulate cell growthand differentiation. These protein products of proto-oncogenes includethe extracellular growth factors, transmembrane growth factor PTKreceptors (RTKs), cytoplasmic PTKs (CTKs) and cytosolic STKs, discussedabove.

In view of the apparent link between PK-related cellular activities andwide variety of human disorders, it is no surprise that a great deal ofeffort is being expended in an attempt to identify ways to modulate PKactivity. Some of these have involved biomimetic approaches using largemolecules patterned on those involved in the actual cellular processes(e.g., mutant ligands (U.S. Pat. No. 4,966,849); soluble receptors andantibodies (Application No. WO 94/10202, Kendall and Thomas, Proc. Nat'lAcad. Sci., 90:10705–10709 (1994), Kim, et al., Nature, 362:841–844(1993)); RNA ligands (Jelinek, et al., Biochemistry, 33:10450–56);Takano, et al., Mol. Bio. Cell, 4:358A (1993); Kinsella, et al., Exp.Cell Res., 199:56–62 (1992); Wright, et al., J. Cellular Phys.,152:448–57) and tyrosine kinase inhibitors (WO 94/03427; WO 92/21660; WO91/15495; WO 94/14808; U.S. Pat. No. 5,330,992; Mariani, et al., Proc.Am. Assoc. Cancer Res., 35:2268 (1994)).

In addition to the above, attempts have been made to identify smallmolecules which act as PK inhibitors. For example, bis-monocylic,bicyclic and heterocyclic aryl compounds (PCT WO 92/20642),vinylene-azaindole derivatives (PCT WO 94/14808) and1-cyclopropyl-4-pyridylquinolones (U.S. Pat. No. 5,330,992) have beendescribed as tyrosine kinase inhibitors. Styryl compounds (U.S. Pat. No.5,217,999), styryl-substituted pyridyl compounds (U.S. Pat. No.5,302,606), quinazoline derivatives (EP Application No. 0 566 266 A1),selenaindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxyliccompounds (PCT WO 92/21660) and benzylphosphonic acid compounds (PCT WO91/15495) have all been described as PTK inhibitors useful in thetreatment of cancer.

SUMMARY

In one embodiment, the invention provides a compound of formula 1

wherein:

Y is N or CR¹²;

R¹ is selected from C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂cycloalkyl, 3–12 membered heteroalicyclic, —O(CR⁶R⁷)_(m)R⁴, —C(O)_(n)R⁴,—C(O)OR⁴, —CN, —NO₂, —S(O)_(n)R⁴, —SO₂NR⁴R, —C(O)NR⁴R⁵, —NR⁴C(O)R⁵,—C(═NR)NR⁴R⁵, C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl; and eachhydrogen in R¹ is optionally substituted by one or more R³ groups;

R² is hydrogen, halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12membered heteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴S(O)_(p)R⁵ or —C(O)NR⁴R⁵, and each hydrogen in R² is optionallysubstituted by one or more R⁸ groups;

R³ is halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)CR⁴R⁵, —C(═NR⁶)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴S(O)_(p)R⁵ or —C(O)NR⁴R⁵, each hydrogen in R³ is optionallysubstituted by one or more R⁸ groups, and R³ groups on adjacent atomsmay combine to form a C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂cycloalkyl or 3–12 membered heteroalicyclic group;

each R⁴, R⁵, R⁶ and R⁷ is independently hydrogen, halogen, C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₁₋₁₂ aryl, 3–12membered heteroalicyclic, 5–12 membered heteroaryl; or any two of R⁴,R⁵, R⁶ and R⁷ bound to the same nitrogen atom may, together with thenitrogen to which they are bound, be combined to form a 3 to 12 memberedheteroalicyclic or 5–12 membered heteroaryl group optionally containing1 to 3 additional heteroatoms selected from N, O, and S; or any two ofR⁴, R⁵, R⁶ and R⁷ bound to the same carbon atom may be combined to forma C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic or 5–12membered heteroaryl group; and each hydrogen in R⁴, R⁵, R⁶ and R⁷ isoptionally substituted by one or more R⁸ groups;

each R⁸ is independently halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic,5–12 membered heteroaryl, —CN, —O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂cycloalkyl, —O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3–12 memberedheteroalicyclic) or —O—(CH₂)_(n)(5–12 membered heteroaryl); and eachhydrogen in R⁸ is optionally substituted by one or more R¹¹ groups;

A¹ is —(CR⁹R¹⁰)_(n)-A² except that:

-   -   (i) when Y is N and R¹ is substituted or unsubstituted aryl or        substituted or unsubstituted heteroaryl, A¹ is —(CR⁹R¹⁰)_(n)-A²        and n is not zero; and    -   (ii) when Y is N and R² is H and A¹ is m-chlorobenzyl, R¹ is not        unsubstituted piperazine;

each R⁹ and R¹⁰ is independently hydrogen, halogen, C₁₋₂ alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴S(O)_(p)R⁵or —C(O)NR⁴R⁵; R⁹ and R¹⁰ may combine to form a C₃₋₁₂ cycloalkyl, 3–12membered heteroalicyclic, C₆₋₁₂ aryl or 5–12 membered heteroaryl ring;and each hydrogen in R⁹ and R¹⁰ is optionally substituted by one or moreR³ groups;

A² is C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂ cycloalkyl or 3–12membered heteroalicyclic, and A² is optionally substituted by one ormore R³ groups;

each R¹¹ is independently halogen, C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₃₋₁₂cycloalkyl, C₁₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂ cycloalkyl,—O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3–12 membered heteroalicyclic),—O—(CH₂)_(n)(5–12 membered heteroaryl) or —CN, and each hydrogen in R¹¹is optionally substituted by one or more groups selected from halogen,—OH, —CN, —C₁₋₂ alkyl which may be partially or fully halogenated,—O—C₁₋₁₂ alkyl which may be partially or fully halogenated, —CO, —SO and—SO₂;

R¹² is hydrogen, halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₃₋₁₂ cycloalkyl, C₁₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12membered heteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴, —NR⁴C(O)R⁴,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴S(O)_(p)R⁵ or —C(O)NR⁴R⁵, and each hydrogen in R¹² is optionallysubstituted by one or more R³ groups;

R¹ and R² or R¹ and R¹² may be combined together to form a C₁₋₁₂ aryl,5–12 membered heteroaryl, C₃₋₁₂ cycloalkyl or 3–12 memberedheteroalicyclic group;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4; and

p is 1 or 2;

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In a particular aspect of this embodiment, Y is N. In a preferredaspect, R¹ is not piperazine. In another preferred aspect, R¹ is notheteroalicyclic.

In another particular aspect of this embodiment, Y is CR¹².

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment, the compound has formula 1a

wherein A² is C₆₋₁₂ aryl or 5–12 membered heteroaryl optionallysubstituted by one or more R³ groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment, R¹ is selected from C₁₋₁₂aryl and 5–12 membered heteroaryl, and each hydrogen in R¹ is optionallysubstituted by one or more R³ groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is selected from C₃₋₁₂ cycloalkyl, 3–12membered heteroalicyclic, —O(CR⁶R⁷)_(n)R⁴, —C(O)R⁴, —C(O)OR⁴, —CN, —NO₂,—S(O)_(m)R⁴, —SO₂NR⁴R⁵, —C(O)NR⁴R⁵, —NR⁴C(O)R⁵, —C(═NR)NR⁴R⁵, C₁₋₉alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl; and each hydrogen in R¹ isoptionally substituted by one or more R³ groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment, A² is substituted by atleast one halogen atom.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment, R² is hydrogen, R⁹ and R¹⁰are independently C₁₋₄ alkyl, and A² is phenyl substituted by at leastone halogen atom.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is a furan, thiopene, pyrrole, pyrroline,pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline,imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole,isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine,piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine,pyrimidine, pyrazine, piperazine, triazine, trithiane or phenyl group,and each hydrogen in R¹ is optionally substituted by one or more R³groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is a furan, thiopene, pyrrole, pyrroline,pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline,imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole,isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine,piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine,pyrimidine, pyrazine, triazine, trithiane or phenyl group, and eachhydrogen in R¹ is optionally substituted by one or more R³ groups. In amore particular aspect, R¹ is not heteroalicyclic.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is a fused ring heteroaryl group, andeach hydrogen in R¹ is optionally substituted by one or more R³ groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is a —SO₂NR⁴R⁵ group.

In another embodiment, the invention provides a compound of formula 2

wherein:

R¹ is selected from C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂cycloalkyl, 3–12 membered heteroalicyclic, —O(CR⁶R⁷),R⁴, —C(O)R⁴,—C(O)OR⁴, —CN, —NO₂, S(O)_(m)R⁴, —SO₂NR⁴R⁵, —C(O)NR⁴R⁵, —NR⁴C(O)R⁵,—C(═NR)NR⁴R⁵, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₈ alkynyl; and eachhydrogen in R¹ is optionally substituted by one or more R³ groups;

R² is hydrogen, halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₃₋₁₂ cycloalkyl, C₁₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12membered heteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁶)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴S(O)_(p)R¹ or —C(O)N R⁴R⁵, and each hydrogen in R² is optionallysubstituted by one or more R⁸ groups;

R³ is halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂cycloalkyl, C₁₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁶)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴S(O)_(p)R⁵ or —C(O)NR⁴R⁵, each hydrogen in R³ is optionallysubstituted by one or more R⁸ groups, and R³ groups on adjacent atomsmay combine to form a C₁₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂cycloalkyl or 3–12 membered heteroalicyclic group;

each R⁴, R⁵, R⁶ and R⁷ is independently hydrogen, halogen, C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₁₋₁₂ aryl, 3–12membered heteroalicyclic, 5–12 membered heteroaryl; or any two of R⁴,R⁵, R₆ and R₇ bound to the same nitrogen atom may, together with thenitrogen to which they are bound, be combined to form a 3 to 12 memberedheteroalicyclic or 5–12 membered heteroaryl group optionally containing1 to 3 additional heteroatoms selected from N, O, and S; or any two ofR⁴, R⁵, R⁶ and R⁷ bound to the same carbon atom may be combined to forma C₃₋₁₂ cycloalkyl, C₁₋₁₂ aryl, 3–12 membered heteroalicyclic or 5–12membered heteroaryl group; and each hydrogen in R⁴, R⁵, R⁶ and R⁷ isoptionally substituted by one or more R⁸ groups;

each R⁸ is independently halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₁₋₁₂ aryl, 3–12 membered heteroalicyclic,5–12 membered heteroaryl, —CN, —O—C₁₋₁₂ alkyl, —O—(CH₂)_(r)C₃₋₁₂cycloalkyl, —O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3–12 memberedheteroalicyclic) or —O—(CH₂)_(n)(5–12 membered heteroaryl); and eachhydrogen in R⁸ is optionally substituted by one or more R¹¹ groups;

A¹ is —(CR⁹R¹⁰)_(n)-A²;

each R⁹ and R¹⁰ is independently hydrogen, halogen, C₁₋₁₂ alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —NR⁴C(O)R⁴, —(CR⁶R⁷)_(n)C(O)OR,—(CR⁶R⁷)_(n)NCR⁴R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴S(O)_(p)R⁵ or —C(O)NR⁴R⁵; R⁹ andR¹⁰ may combine to form a C₁₋₁₂ cycloalkyl, 3–12 memberedheteroalicyclic, C₁₋₁₂ aryl or 5–12 membered heteroaryl ring; and eachhydrogen in R⁹ and R¹⁰ is optionally substituted by one or more R³groups;

A² is C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂ cycloalkyl or 3–12membered heteroalicyclic, and A² is optionally substituted by one ormore R³ groups;

each R¹¹ is independently halogen, C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₃₋₁₂cycloalkyl, C₁₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂ cycloalkyl,—O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3–12 membered heteroalicyclic),—O—(CH₂)_(n)(5–12 membered heteroaryl) or —CN, and each hydrogen in R¹¹is optionally substituted by one or more groups selected from halogen,—OH, —CN, —C₁₋₁₂ alkyl which may be partially or fully halogenated,—O—C₁₋₁₂ alkyl which may be partially or fully halogenated, —CO, —SO and—SO₂;

R¹² is hydrogen, halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₃₋₁₂ cycloalkyl, C₁₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12membered heteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂,—NR⁴R⁵—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴,—NR⁴C(O)R⁵, —(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR)NR⁴R⁵,—NR⁴C(O)NR⁵R⁶, —NR⁴S(O)_(p)R⁵ or —C(O)NR⁴R⁵, and each hydrogen in R¹² isoptionally substituted by one or more R³ groups;

R¹ and R² or R¹ and R¹² may be combined together to form a C₆₋₁₂ aryl,5–12 membered heteroaryl, C₃₋₁₂ cycloalkyl or 3–12 memberedheteroalicyclic group;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4; and

p is 1 or 2;

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In a particular aspect of this embodiment, the compound has formula 2a

wherein A² is C₆₋₁₂ aryl or 5–12 membered heteroaryl optionallysubstituted by one or more R³ groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment, R¹ is selected from C₆₋₁₂aryl and 5–12 membered heteroaryl, and each hydrogen in R¹ is optionallysubstituted by one or more R³ groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is selected from C₃₋₁₂ cycloalkyl, 3–12membered heteroalicyclic, —O(CR⁶R⁷)_(n)R⁴, —C(O)R⁴, —C(O)OR⁴, —CN, —NO₂,—S(O)_(m)R⁴, —SO₂NR⁴R⁵, —C(O)NR⁴R⁵, —NR⁴C(O)R⁵, —C(═NR)NR⁴R⁵, C₁₋₈alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl; and each hydrogen in R¹ isoptionally substituted by one or more R³ groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment, A² is substituted by atleast one halogen atom.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment, R² is hydrogen, R⁹ and R¹⁰are independently C₁₋₄ alkyl, and A² is phenyl substituted by at leastone halogen atom.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is a furan, thiopene, pyrrole, pyrroline,pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline,imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole,isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine,piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine,pyrimidine, pyrazine, piperazine, triazine, trithiane or phenyl group,and each hydrogen in R¹ is optionally substituted by one or more R³groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is a fused ring heteroaryl group, andeach hydrogen in R¹ is optionally substituted by one or more R³ groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is a —SO₂NR⁴R⁵ group.

In another embodiment, the invention provides a compound of formula 3

wherein:

R¹ is selected from C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂cycloalkyl, 3–12 membered heteroalicyclic, —O(CR⁵R⁷)_(n)R⁴, —C(O)R⁴,—C(O)OR⁴, —CN, —NO₂, S(O)_(m)R⁴, —SO₂NR⁴R⁵, —C(O)NR⁴R⁵, —NR⁴C(O)R⁵,—C(═NR⁶)NR⁴R⁵, C₁₋₄ alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl; and eachhydrogen in R¹ is optionally substituted by one or more R³ groups;

R² is hydrogen, halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12membered heteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁶)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴S(O)_(p)R⁵ or —C(O)NR⁴R⁵, and each hydrogen in R² is optionallysubstituted by one or more R⁸ groups;

R³ is halogen, C₁₋₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁵)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴S(O)_(p)R⁵ or —C(O)NR⁴R⁵, each hydrogen in R³ is optionallysubstituted by one or more R⁸ groups, and R³ groups on adjacent atomsmay combine to form a C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂cycloalkyl or 3–12 membered heteroalicyclic group;

each R⁴, R⁵, R⁶ and R⁷ is independently hydrogen, halogen, C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12membered heteroalicyclic, 5–12 membered heteroaryl; or any two of R⁴,R⁵, R⁶ and R⁷ bound to the same nitrogen atom may, together with thenitrogen to which they are bound, be combined to form a 3 to 12 memberedheteroalicyclic or 5–12 membered heteroaryl group optionally containing1 to 3 additional heteroatoms selected from N, O, and S; or any two ofR⁴, R⁵, R⁶ and R⁷ bound to the same carbon atom may be combined to forma C₃₋₁₂ cycloalkyl, C₁₋₁₂ aryl, 3–12 membered heteroalicyclic or 5–12membered heteroaryl group; and each hydrogen in R⁴, R⁵, R⁶ and R⁷ isoptionally substituted by one or more R⁸ groups;

each R⁸ is independently halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic,5–12 membered heteroaryl, —CN, —O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂cycloalkyl, —O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3–12 memberedheteroalicyclic) or —O—(CH₂)_(n)(5–12 membered heteroaryl); and eachhydrogen in R⁸ is optionally substituted by one or more R¹¹ groups;

A¹ is —(CR⁹R¹⁰)_(n)-A² except that:

-   -   (i) when R¹ is substituted or unsubstituted aryl or substituted        or unsubstituted heteroaryl, A¹ is —(CR⁹R¹⁰)_(n)-A² and n is not        zero; and    -   (ii) when R² is H and A¹ is m-chlorobenzyl, R¹ is not        unsubstituted piperazine;

each R⁹ and R¹⁰ is independently hydrogen, halogen, C₁₋₁₂ alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴S(O)_(p)R⁵or —C(O)NR⁴R⁵; R⁹ and R¹⁰ may combine to form a C₃₋₁₂ cycloalkyl, 3–12membered heteroalicyclic, C₆₋₁₂ aryl or 5–12 membered heteroaryl ring;and each hydrogen in R⁹ and R¹⁰ is optionally substituted by one or moreR³ groups;

A² is C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂ cycloalkyl or 3–12membered heteroalicyclic, and A² is optionally substituted by one ormore R³ groups;

each R¹¹ is independently halogen, C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂ cycloalkyl,—O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3–12 membered heteroalicyclic),—O—(CH₂)_(n)(5–12 membered heteroaryl) or —CN, and each hydrogen in R¹¹is optionally substituted by one or more groups selected from halogen,—OH, —CN, —C₁₋₁₂ alkyl which may be partially or fully halogenated,—O—C₁₋₁₂ alkyl which may be partially or fully halogenated, —CO, —SO and—SO₂;

R¹ and R² may be combined together to form a C₆₋₁₂ aryl, 5–12 memberedheteroaryl, C₃₋₁₂ cycloalkyl or 3–12 membered heteroalicyclic group;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4; and

p is 1 or 2;

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In a particular aspect of this embodiment, the compound has formula 3a

wherein A² is C₆₋₁₂ aryl or 5–12 membered heteroaryl optionallysubstituted by one or more R³ groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment, R¹ is selected from C₆₋₁₂aryl and 5–12 membered heteroaryl, and each hydrogen in R¹ is optionallysubstituted by one or more R³ groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is selected from C₃₋₁₂ cycloalkyl, 3–12membered heteroalicyclic, —O(CR⁶R⁷)_(n)R⁴, —C(O)R⁴, —C(O)OR⁴, —CN, —NO₂,—S(O)_(m)R⁴, —SO₂NR⁴R⁵, —C(O)NR⁴R⁵, —NR⁴C(O)R⁵, —C(═NR)NR⁴R⁵, C₁₋₄alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl; and each hydrogen in R¹ isoptionally substituted by one or more R³ groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment, A² is substituted by atleast one halogen atom.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment, R² is hydrogen, R⁹ and R¹⁰are independently C₁₋₄ alkyl, and A² is phenyl substituted by at leastone halogen atom.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is a furan, thiopene, pyrrole, pyrroline,pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline,imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole,isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine,piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine,pyrimidine, pyrazine, piperazine, triazine, trithiane or phenyl group,and each hydrogen in R¹ is optionally substituted by one or more R³groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is a furan, thiopene, pyrrole, pyrroline,pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline,imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole,isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine,piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine,pyrimidine, pyrazine, triazine, trithiane or phenyl group, and eachhydrogen in R¹ is optionally substituted by one or more R³ groups. Instill more particular aspects, R¹ is not heteroalicyclic.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is a fused ring heteroaryl group, andeach hydrogen in R¹ is optionally substituted by one or more R³ groups.

In particular aspects of this embodiment, and in combination with anyother particular aspects of this embodiment not inconsistent with thefollowing definition of R¹, R¹ is a —SO₂NR⁴R⁵ group.

In another embodiment, the invention provides a compound of formula 4

wherein:

R¹ is selected from C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂cycloalkyl, 3–12 membered heteroalicyclic, —O(CR⁶R⁷)_(n)R⁴, —C(O)R⁴,—C(O)OR⁴, —CN, —NO₂, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —C(O)NR⁴R⁵, —NR⁴C(O)R⁵,—C(═NR⁶)NR⁴R⁵, C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl; and eachhydrogen in R¹ is optionally substituted by one or more R³ groups;

R³ is halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(r)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁶)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴S(O)_(p)R⁵ or —C(O)NR⁴R⁵, each hydrogen in R³ is optionallysubstituted by one or more R⁸ groups, and R³ groups on adjacent atomsmay combine to form a C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂cycloalkyl or 3–12 membered heteroalicyclic group;

each R⁴, R⁵, R⁶ and R⁷ is independently hydrogen, halogen, C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₁₋₁₂ aryl, 3–12membered heteroalicyclic, 5–12 membered heteroaryl; or any two of R⁴,R⁵, R⁶ and R⁷ bound to the same nitrogen atom may, together with thenitrogen to which they are bound, be combined to form a 3 to 12 memberedheteroalicyclic or 5–12 membered heteroaryl group optionally containing1 to 3 additional heteroatoms selected from N, O, and S; or any two ofR⁴, R⁵, R⁶ and R⁷ bound to the same carbon atom may be combined to forma C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic or 5–12membered heteroaryl group; and each hydrogen in R⁴, R⁵, R⁶ and R⁷ isoptionally substituted by one or more R⁸ groups;

each R⁸ is independently halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₁₋₁₂ aryl, 3–12 membered heteroalicyclic,5–12 membered heteroaryl, —CN, —O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂cycloalkyl, —O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3–12 memberedheteroalicyclic) or —O—(CH₂)_(n)(5–12 membered heteroaryl); and eachhydrogen in R⁹ is optionally substituted by one or more R¹¹ groups;

each R⁹ and R¹⁰ is independently hydrogen, halogen, C₁₋₁₂ alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴S(O)_(p)R⁵or —C(O)NR⁴R⁵; R⁹ and R¹⁰ may combine to form a C₃₋₁₂ cycloalkyl, 3–12membered heteroalicyclic, C₆₋₁₂ aryl or 5–12 membered heteroaryl ring;and each hydrogen in R⁹ and R¹⁰ is optionally substituted by one or moreR³ groups;

A² is C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂ cycloalkyl or 3–12membered heteroalicyclic, and A² is optionally substituted by one ormore R³ groups;

each R¹¹ is independently halogen, C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₃₋₁₂cycloalkyl, C₁₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂ cycloalkyl,—O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3–12 membered heteroalicyclic),—O—(CH₂)_(n)(5–12 membered heteroaryl) or —CN, and each hydrogen in R¹¹is optionally substituted by one or more groups selected from halogen,—OH, —CN, —C₁₋₁₂ alkyl which may be partially or fully halogenated,—O—C₁₋₁₂ alkyl which may be partially or fully halogenated, —CO, —SO and—SO₂;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4; and

p is 1 or 2;

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In a particular aspect of this embodiment, A² is C₆₋₁₂ aryl or 5–12membered heteroaryl optionally substituted by one or more R³ groups.

In other particular aspects of this embodiment, preferred substituentsand groups of substituents include those defined in particular aspectsof the previous embodiments.

In another embodiment, the invention provides a compound of formula 5

wherein:

R¹ is selected from C₁₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂cycloalkyl, 3–12 membered heteroalicyclic, —O(CR⁶R⁷)_(n)R⁴, —C(O)R⁴,—C(O)OR⁴, —CN, —NO₂, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —C(O)NR⁴R⁵, —NR⁴C(O)R⁵,—C(═NR⁶)NR⁴R⁵, C₁₋₈ alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl; and eachhydrogen in R³ is optionally substituted by one or more R³ groups;

R³ is halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(r)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁶)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴S(O)_(p)R⁵ or —C(O)NR⁴R⁵, each hydrogen in R³ is optionallysubstituted by one or more R⁸ groups, and R³ groups on adjacent atomsmay combine to form a C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂cycloalkyl or 3–12 membered heteroalicyclic group;

each R⁴, R⁵, R⁶ and R⁷ is independently hydrogen, halogen, C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12membered heteroalicyclic, 5–12 membered heteroaryl; or any two of R⁴,R⁵, R⁶ and R⁷ bound to the same nitrogen atom may, together with thenitrogen to which they are bound, be combined to form a 3 to 12 memberedheteroalicyclic or 5–12 membered heteroaryl group optionally containing1 to 3 additional heteroatoms selected from N, O, and S; or any two ofR⁴, R⁵, R⁶ and R⁷ bound to the same carbon atom may be combined to forma C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic or 5–12membered heteroaryl group; and each hydrogen in R⁴, R⁵, R⁶ and R⁷ isoptionally substituted by one or more R⁸ groups;

each R⁸ is independently halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic,5–12 membered heteroaryl, —CN, —O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂cycloalkyl, —O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3–12 memberedheteroalicyclic) or —O—(CH₂)_(n)(5–12 membered heteroaryl); and eachhydrogen in R⁸ is optionally substituted by one or more R¹¹ groups;

each R⁹ and R¹⁰ is independently hydrogen, halogen, C₁₋₁₂ alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)CR⁴R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴S(O)_(p)R⁵ or—C(O)NR⁴R⁵; R⁹ and R¹⁰ may combine to form a C₃₋₁₂ cycloalkyl, 3–12membered heteroalicyclic, C₆₋₁₂ aryl or 5–12 membered heteroaryl ring;and each hydrogen in R⁹ and R¹⁰ is optionally substituted by one or moreR³ groups;

A² is C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂ cycloalkyl or 3–12membered heteroalicyclic, and A² is optionally substituted by one ormore R³ groups; except that when R², R⁹ and R¹⁰ are all H and A² ism-chlorophenyl, R¹ is not unsubstituted piperazine;

each R¹¹ is independently halogen, C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₃₋₁₂cycloalkyl, C₁₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂ cycloalkyl,—O—(CH₂)_(n)C₁₋₁₂ aryl, —O—(CH₂)_(n)(3–12 membered heteroalicyclic),—O—(CH₂)_(n)(5–12 membered heteroaryl) or —CN, and each hydrogen in R¹¹is optionally substituted by one or more groups selected from halogen,—OH, —CN, —C₁₋₁₂ alkyl which may be partially or fully halogenated,—O—C₁₋₁₂ alkyl which may be partially or fully halogenated, —CO, —SO and—SO₂;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4; and

p is 1 or 2;

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In a particular aspect of this embodiment, A² is C₆₋₁₂ aryl or 5–12membered heteroaryl optionally substituted by one or more R³ groups.

In other particular aspects of this embodiment, preferred substituentsand groups of substituents include those defined in particular aspectsof the previous embodiments.

In another embodiment, the invention provides a compound selected fromthe group consisting of:4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenol;3-(2,6-dichloro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(1H-indol-4-yl)-pyridin-2-ylamine;3-[2-chloro-6-(1H-indol-4-yl)-benzyloxy]-5-(1H-indol-4-yl)-pyridin-2-ylamine;2-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-pyrrole-1-carboxylicacid tert-butyl ester;3-(2,6-dichloro-benzyloxy)-5-(1H-pyrrol-2-yl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(4-fluoro-phenyl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-phenyl-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(2-fluoro-phenyl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(3-fluoro-phenyl)-pyridin-2-ylamine;5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine;N-4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide;N-{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-acetamide;3-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenol;3-(2,6-dichloro-benzyloxy)-5-(4-methoxy-phenyl)-pyridin-2-ylamine;5-(3-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(3-trifluoromethoxy-phenyl)-pyridin-2-ylamine;2-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenol;3-(2,6-dichloro-benzyloxy)-5-(2-phenoxy-phenyl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(3,4-difluoro-phenyl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(3-isopropyl-phenyl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(2-methoxy-phenyl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(4-trifluoromethyl-phenyl)-pyridin-2-ylamine;N-{2-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-methanol;5-benzo[1,3]dioxol-5-yl-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(2-trifluoromethoxy-phenyl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(4-methyl-thiophen-2-yl)-pyridin-2-ylamine;5-(2-benzyloxy-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(3-methoxy-phenyl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(1H-indol-2-yl)-pyridin-2-ylamine;5-(4-benzyloxy-3-fluoro-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine;4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid;4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-diethylamino-ethyl)-benzamide;4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(3-diethylamino-propyl)-benzamide;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl[(3S)-3-cyclopropylaminomethyl-piperidin-1-yl]-methanone;4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide;(4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-(3-fluoro-piperidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-cyclopropyl-piperazin-1-yl)-methanone;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-{(2R)-2-[(cyclopropylmethyl-amino)-methyl]-pyrrolidin-1-yl)methanone;4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-cyclopropylmethyl-N-(2R)-pyrrolidin-2-ylmethyl-benzamide;4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-hydroxy-3-pyrrolidin-1-yl-propyl)-N-methyl-benzamide;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-{(2S)-2-[(3R)-3-hydroxy-pyrrolidin-1-ylmethyl]-pyrrolidin-1-yl)methanone;3-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid;{3-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy)-aceticacid;2-{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy}-1-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanone;2-{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy)-1-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanone;3-(2,6-dichloro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(3-morpholin-4-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(3-piperidin-1-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(3-pyrrolidin-1-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-(3-diethylaminomethyl-1H-indol-5-yl)-pyridin-2-ylamine;(1-{5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-(3R)-pyrrolidin-3-yl)-carbamicacid tert-butyl ester;3-(2,6-dichloro-benzyloxy)-5-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-5-yl]-pyridin-2-ylamine;N-(1-{5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-(3R)-pyrrolidin-3-yl)-acetamide;1-(4-{5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-piperazin-1-yl)-ethanone;3-(2-chloro-3,6-difluoro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylamine;1-(4-{5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-piperazin-1-yl)-ethanone;3-(2-chloro-3,6-difluoro-benzyloxy)-5-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-5-yl]-pyridin-2-ylamine;N-(1-{5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-(3S)-pyrrolidin-3-yl)-acetamide;3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-piperidin-1-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine;3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-morpholin-4-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine;3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-pyrrolidin-1-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine;5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylicacid ethyl ester;5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylicacid;{5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-2-yl}-(4-methyl-piperazin-1-yl)-methanone;(5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-2-yl}[(3R)-3-dimethylamino-pyrrolidin-1-yl]-methanone;{5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-2-yl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide;5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylicacid (2-morpholin-4-yl-ethyl)-amide;(1-{5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carbonyl}-(3S)-pyrrolidin-3-yl)-carbamicacid tert-butyl ester;{5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-2-yl}[(3S)-3-amino-pyrrolidin-1-yl]-methanone;5-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide;4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenol;3-benzyloxy-5-phenyl-pyridin-2-ylamine;3-(3-methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine;3-(2-chloro-4-fluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine;3-(2-chloro-benzyloxy)-5-phenyl-pyridin-2-ylamine;3-(2,5-dichloro-benzyloxy)-5-phenyl-pyridin-2-ylamine;3-(2-chloro-5-trifluoromethyl-benzyloxy)-5-phenyl-pyridin-2-ylamine;3-(2,4-dichloro-5-fluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine;3-(2-chloro-3-trifluoromethyl-benzyloxy)-5-phenyl-pyridin-2-ylamine;3-(2-chloro-3,6-difluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine;3-(3,4-dichloro-benzyloxy)-5-phenyl-pyridin-2-ylamine;2-(2-amino-5-phenyl-pyridin-3-yloxymethyl)-benzonitrile;3-(2-chloro-6-fluoro-3-methyl-benzyloxy)-5-phenyl-pyridin-2-ylamine;5-Phenyl-3-(2,3,6-trifluoro-benzyloxy)-pyridin-2-ylamine;3-(2,6-difluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine;3-(2,6-difluoro-3-methyl-benzyloxy)-5-phenyl-pyridin-2-ylamine;3-(3-chloro-2,6-difluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine;3-(2-chloro-6-fluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine;3-(3-Fluoro-4-methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine;N-[3-(2-amino-5-phenyl-pyridin-3-yloxymethyl)-phenyl]-methanesulfonamide;5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3-nitro-benzyloxy)-pyridin-2-ylamine;5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(naphthalen-1-ylmethoxy)-pyridin-2-ylamine;3-(2-chloro-3,6-difluoro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;2-[2-amino-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-3-yloxy)-N-(4-isopropyl-phenyl)-2-phenyl-acetamide;3-(5-chloro-benzo[b]thiophen-3-ylmethoxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;(4-[6-amino-5-(4-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-fluoro-6-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;(4-[6-amino-5-(5-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;(4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-ylphenyl)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-bromo-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl][(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenol;3-(2,6-difluoro-benzyloxy)-5-(1H-indol-4-yl)-pyridin-2-ylamine;3-(2,6-difluoro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid;{4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-aceticacid ethyl ester;{4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy)aceticacid;2-{4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-1-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanone;2-{4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy)-1-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanone;4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenol;4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenol;4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenol;2-[2-amino-5-(4-hydroxy-phenyl)-pyridin-3-yloxymethyl]-benzonitrile;4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenol;4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenol;4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-y]-phenol;N-{4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-phenyl)methanesulfonamide;2-[2-amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-benzamide;2-[2-amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-benzoicacid;N-(4-{6-amino-5-[2-(4-methyl-piperazine-1-carbonyl)-benzyloxy]-pyridin-3-yl}-phenyl)-methanesulfonamide;2-[2-amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-N-(2-hydroxy-ethyl)-benzamide;2-[2-amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-N-isobutyl-benzamide;4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid;{4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl)[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl)[(3S)-3-amino-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;1-(4-{4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoyl)piperazin-1-yl)-ethanone;4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide;4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-benzoic acid;{4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;{4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl)(4-methyl-piperazin-1-yl)-methanone;1-(4-{4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-benzoyl)piperazin-1-yl)-ethanone;4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide;4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-benzoic acid;2-{2-amino-5-[4-((2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile;2-{2-amino-5-[4-((2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile;2-{2-amino-5-[4-((3S)-3-dimethylamino-pyrrolidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile;2-{2-amino-5-[4-((3S)-3-amino-pyrrolidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile;2-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile;2-{2-amino-5-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile;2-{5-[4-(4-acetyl-piperazine-1-carbonyl)-phenyl]-2-amino-pyridin-3-yloxymethyl}-benzonitrile;4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide;4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide;4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid;{4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;{4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;1-(4-{4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-benzoyl)piperazin-1-yl)-ethanone;4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide;4-[6-amino-5-(2,4-dichloro-benzyloxy)pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide;4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzoic acid;{4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone;[(3S)-3-amino-pyrrolidin-1-yl]-4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-methanone;{4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;{4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;1-(44-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzoyl}-piperazin-1-yl)-ethanone;4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide;4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide;4-[6-amino-5-(4-#tert!-butyl-benzyloxy)-pyridin-3-yl]-benzoic acid;{4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenyl}[(3R)-3-dimethylamino-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;1-(4-{4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-benzoyl)piperazin-1-yl)-ethanone;4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide;4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide;4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid;{4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;1-(4-{4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-benzoyl)piperazin-1-yl)-ethanone;4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide;4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-y]-benzoicacid;{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;(4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-amino-piperidin-1-yl)-methanone;{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone;{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;(4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3R)-3-amino-pyrrolidin-1-yl]-methanone;{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone;4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide;4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(3-pyrrolidin-1-yl-propyl)-benzamide;4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide;3-[6-amino-5-(2chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid;{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl)(4-amino-piperidin-1-yl)-methanone;{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone;{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone;{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3R)-3-amino-pyrrolidin-1-yl]-methanone;{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-amino-pyrrolidin-1-yl]-methanone;3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide;3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(3-pyrrolidin-1-yl-propyl)-benzamide;3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzamide;3-(2-chloro-3,6-difluoro-benzyloxy)-5-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylamine;5-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-3-(2-fluoro-6-trifluoromethyl-benzyloxy)-pyridin-2-ylamine;2-diethylamino-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-cyclopropylamino-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-Pyrrolidin-1-yl-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-(4-hydroxy-piperidin-1-yl)-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-morpholin-4-yl-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl)amide;2-Piperidin-1-yl-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-dimethylamino-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl)amide;2-(4-acetyl-piperazin-1-yl)-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-(cyclopropylmethyl-amino)-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl)-amide;2-[(3R)-3-hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-[(2S)-2-hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-[4-(2-hydroxy-acetyl)-piperazin-1-yl]-ethanesulfonic acid(4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-(4-acetyl-piperazin-1-yl)-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-Pyrrolidin-1-yl-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-morpholin-4-yl-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-diethylamino-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-dimethylamino-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-Piperidin-1-yl-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-[(3R)-3-hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-(4-hydroxy-piperidin-1-yl)-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-[4-(2-hydroxy-acetyl)-piperazin-1-yl]-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl)amide;2-[(3R)-3-hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-(cyclopropylmethyl-amino)-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;2-cyclopropylamino-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide;3-(2-chloro-3,6-difluoro-benzyloxy)-5-(2-dimethylaminomethyl-phenyl)-pyridin-2-ylamine;compound with trifluoro-acetic acid;3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-pyrrolidin-1-yl-phenyl)-pyridin-2-ylamine;compound with trifluoro-acetic acid;N-{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl)methanesulfonamide;compound with trifluoro-acetic acid;5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophene-2-carboxylicacid;{5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophen-2-yl}-(4-methyl-piperazin-1-yl)-methanone;{5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophen-2-yl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophene-2-carboxylicacid (1-methyl-piperidin-4-yl)-amide;{5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophen-2-yl}-(3,5-dimethyl-piperazin-1-yl)-methanone;5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophene-2-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide;{5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophen-2-yl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzoicacid;{4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide;{4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone;{4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl)(3-dimethylamino-pyrrolidin-1-yl)-methanone;{4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-#N!-(2-morpholin-4-yl-ethyl)-benzamide;{4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzamide;2-Piperidin-1-yl-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-(4-hydroxy-piperidin-1-yl)-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-dimethylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-cyclopropylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-[(3R)-3-amino-pyrrolidin-1-yl)]-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone;2-cyclopropylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-dimethylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-[(3R)-3-hydroxy-pyrrolidin-1-yl)]-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;and pharmaceutically acceptable salts, hydrates and solvates thereof.

In another embodiment, the invention provides a compound selected fromthe group consisting of:4-[5-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-phenol;3-(2,6-dichloro-benzyloxy)-5-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-pyrazin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine;3-(2,6-dichloro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine;5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyrazin-2-ylamine;4-[5-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-benzoic acid;{4-[5-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;{4-[5-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;2-morpholin-4-yl-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-piperidin-1-yl-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-pyrrolidin-1-yl-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-[(3R)-3-Hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-[(2S)-2-Hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-(cyclopropylmethyl-amino)-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-dimethylamino-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-diethylamino-ethanesulfonic acid{4-5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-(4-acetyl-piperazin-1-yl)-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-[4-(2-Hydroxy-acetyl)-piperazin-1-yl]-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-cyclopropylamino-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-[(3R)-3-Hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-(4-acetyl-piperazin-1-yl)-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl)amide;2-piperidin-1-yl-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-diethylamino-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-morpholin-4-yl-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-pyrrolidin-1-yl-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-dimethylamino-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-[4-(2-Hydroxy-acetyl)-piperazin-1-yl]-ethanesulfonic acid(3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-(cyclopropylmethyl-amino)-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}amide;2-[(3R)-3-Hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid(3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;2-cyclopropylamino-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide;4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzoicacid;{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzamide;4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(3-pyrrolidin-1-yl-propyl)-benzamide;{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone;{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-methanone;{-4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone;{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(3-morpholin-4-yl-propyl)-benzamide;4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(1-methyl-piperidin-4-yl)-benzamide;4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzoicacid;{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3R)-3-amino-pyrrolidin-1-yl]-methanone;{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone;{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone;3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(3-morpholin-4-yl-propyl)-benzamide;{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone;3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(1-methyl-piperidin-4-yl)-benzamide;{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(2S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone;3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzamide;3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(3-pyrrolidin-1-propyl)-benzamide;3-(2-chloro-3,6-difluoro-benzyloxy)-5-(1H-indol-5-yl)-pyrazin-2-ylamine;3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-pyrrolidin-1-ylmethyl-1H-indol-5-yl)-pyrazin-2-ylamine;3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-diethylaminomethyl-1H-indol-5-yl)-pyrazin-2-ylamine;1-(4-{5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-1H-indol-3-ylmethyl)piperazin-1-yl)-ethanone;3-(2-chloro-3,6-difluoro-benzyloxy)-5-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-5-yl]-pyrazin-2-ylamine;N-(1-{5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-1H-indol-3-ylmethyl}-(3S)-pyrrolidin-3-yl)-acetamide;3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-piperidin-1-ylmethyl-1H-indol-5-yl)-pyrazin-2-ylamine;3-(2-chloro-3,6-difluoro-benzyloxy)-5-(3-morpholin-4-ylmethyl-1H-indol-5-yl)-pyrazin-2-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-2-methyl-propoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine;compound with trifluoro-acetic acid;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine;compound with trifluoro-acetic acid;N-(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-methanesulfonamide;2-pyrrolidin-1-yl-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;2-piperidin-1-yl-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;2-(cyclopropylmethyl-amino)-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;2-[(3R)-3-Hydroxy-pyrrolidin-1-y]-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;2-[(2S)-2-Hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;2-dimethylamino-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;2-morpholin-4-yl-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;2-diethylamino-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;2-cyclopropylamino-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid;(3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-[(3S)-3-amino-pyrrolidin-1-yl)-m-ethanone;(3-555-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-[(3R)-3-amino-pyrrolidin-1-yl)-m-ethanone;(3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzamide;(3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylphenyl)-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid;3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;3-{5-amino-6-[-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;(3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;4-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzoicacid;4-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;4-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-N-(1-methyl-piperidin-4-yl)-benzamide;and pharmaceutically acceptable salts, hydrates and solvates thereof.

In another embodiment, the invention provides a compound selected fromthe group consisting of:(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-benzamide;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy)-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-amino-piperidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-hydroxy-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-diethylamino-ethyl)-benzamide;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}benzamide;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-y{)-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy)-pyridin-3-yl}-N-(3-morpholin-4-yl-propyl)-benzamide;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;2-diethylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-piperidin-1-yl-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-(cyclopropylmethyl-amino)-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy)-pyridin-3-yl}-phenyl)-amide;2-((R)-3-Hydroxy-pyrrolidin-1-yl)-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-cyclopropylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-diethylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy)-pyridin-3-yl}-phenyl)-amide;4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl)benzoicacid;4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy)-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-y!)phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone;3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid;(3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;(3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone;3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;(3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;(3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone;3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl)-N-(2-morpholin-4-yl-ethyl)-benzamide;(3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-{4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl)pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-3-morpholin-4-yl-propan-2-ol;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-diethylamino-ethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(1-methyl-piperidin-3-ylmethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-diisopropylamino-ethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(1-methyl-piperidin-4-yloxy)-phenyl]-pyridin-2-ylamine;N-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl)-phenyl)-methanesulfonamide;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-[4-(1,1-dioxo-1lambda*6*-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylamine;N-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanesulfonamide;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-phenyl-pyridin-2-ylamine;N-(4-{6-amino-5-[(R)-1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanesulfonamide;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-thiophen-3-yl-pyridin-2-ylamine;5-benzo[b]thiophen-2-yl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;4-methyl-piperazine-1-carboxylic acid (4-{l-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-phenyl)-amide;1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea;1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-hydroxy-ethyl)-urea;1-(4-(6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea;(R)-3-amino-pyrrolidine-1-carboxylic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;(S)-3-amino-pyrrolidine-1-carboxylic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}phenyl)-amide;1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(1-methyl-piperidin-4-yl)-urea;1-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(1-methyl-piperidin-4-yl)-urea;(R)-3-amino-pyrrolidine-1-carboxylic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;(S)-3-amino-pyrrolidine-1-carboxylic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;1-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-hydroxy-ethyl)-urea;4-methyl-piperazine-1-carboxylic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;1-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea;1-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea;(R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzamide;3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl}-benzamide;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone;4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid;4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl)benzamide;4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-aminopyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-amide;4-methyl-piperazine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-amide;4-pyrrolidin-1-yl-piperidine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-amide;(3R,5S)-3,5-dimethyl-piperazine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-amide;1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-3-(1-methyl-piperidin-4-yl)-urea;1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-3-(3-pyrrolidin-1-yl-propyl)-urea;1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea;1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-3-(2-morpholin-4-yl-ethyl)-urea;1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-3-(3-morpholin-4-yl-propyl)-urea;(R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-amide;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-dimethylamino-prop-1-ynyl)-pyridin-2-ylamine;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)prop-2-ynyl)-urea;N-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-2-piperidin-1-yl-acetamide;N-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-2-morpholin-4-yl-acetamide;N-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-2-pyrrolidin-1-yl-acetamide;N-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-2-((R)-3-hydroxy-pyrrolidin-1-yl)-acetamide;N-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-2-(4-hydroxy-piperidin-1-yl)-acetamide;N-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-2-dimethylamino-acetamide;N-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)prop-2-ynyl)-2-diethylamino-acetamide;2-(4-acetyl-piperazin-1-yl)-N-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]pyridin-3-yl}-prop-2-ynyl)-acetamide;4-methyl-piperazine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-amide;(3R,5S)-3,5-dimethyl-piperazine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-1,1-dimethyl-prop-2-ynyl)-amide;(R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-amide;(S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-amide;1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-3-(2-morpholin-4-yl-ethyl)-urea;1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea;4-pyrrolidin-1-yl-piperidine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-1,1-dimethyl-prop-2-ynyl)-amide;3-(6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-propynoicacid cyclohexylamide;3-(6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-propynoicacid isopropylamide;4-(3-amino-3-methyl-but-1-ynyl)-2-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-phenylamine;(4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-y}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;(4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy)-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-morpholin-4-yl-propyl)-benzamide;6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-nicotinonitrile;6-amino-5-[1-(2,6-dichloro-3-cyano-phenyl)-ethoxy]-nicotinonitrile;5-aminomethyl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;(R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylmethylamide;N-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylmethyl}-methanesulfonamide;N-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylmethyl}-acetamide;N-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylmethyl}-4-methyl-benzenesulfonamide;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-vinyl-pyridin-2-ylamine;(S)-1-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-ethane-1,2-diol;(R)-1-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-ethane-1,2-diol;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-pyrazol-4-yl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(2-diisopropylamino-ethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamine;5-bromo-3-(3-fluoro-2-methoxy-benzyloxy)-pyridin-2-ylamine;5-bromo-3-[1-(3-fluoro-2-methoxy-phenyl)-ethoxy]-pyridin-2-ylamine;{4-[6-amino-5-(3-fluoro-2-methoxy-benzyloxy)-pyridin-3-yl]-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(3-fluoro-2-methoxy-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;5-bromo-3-(3-fluoro-2-isopropoxy-benzyloxy)-pyridin-2-ylamine;{4-[6-amino-5-(3-fluoro-2-isopropoxy-benzyloxy)-pyridin-3-yl]-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;5-(4-amino-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-aceticacid methyl ester;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-aceticacid;2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-1-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-ethanone;2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-1-((R)-3-hydroxy-pyrrolidin-1-yl}-ethanone;4-[2-(4-{6-amino-5-[-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-phenoxy)-acetyl]-piperazine-1-carboxylicacid tert-butyl ester;2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-1-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethanone;5-bromo-3-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-pyridin-2-ylamine;{4-[6-amino-5-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-pyridin-3-yl]-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;3-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-2-ylamine;N-{4-[6-amino-5-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide;3-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-5-(1H-pyrazol-4-yl)-pyridin-2-ylamine;5-bromo-3-[1-(2-chloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;3-[1-(2-chloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-2-ylamine;5′-benzyloxy-[2,3]bipyridinyl-6′-ylamine;5-benzyloxy-[3,3′]bipyridinyl-6-ylamine;3-benzyloxy-5-pyrimidin-5-yl-pyridin-2-ylamine;5-benzyloxy-[3,3′]bipyridinyl-6,6′-diamine;5′-(2-chloro-benzyloxy)-[2,3′]bipyridinyl-6′-ylamine;5-(2-chloro-benzyloxy)-[3,3′]bipyridinyl-6-ylamine;3-(2-chloro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine;5-(2-chloro-benzyloxy)-[3,3′]bipyridinyl-6,6′-diamine;5′-(4-chloro-benzyloxy)-[2,3′]bipyridinyl-6′-ylamine;5-(4-chloro-benzyloxy)-[3,3′]bipyridinyl-6-ylamine;3-(4-chloro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine;5-(4-chloro-benzyloxy)-[3,3′]bipyridinyl-6,6′-diamine;5′-(2-chloro-3,6-difluoro-benzyloxy)-[2,3′]bipyridinyl-6′-ylamine;5-(2-chloro-3,6-difluoro-benzyloxy)-[3,3′]bipyridinyl-6-ylamine;5-(2-chloro-3,6-difluoro-benzyloxy)-[3,4′]bipyridinyl-6-ylamine;3-(2-chloro-3,6-difluoro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine;5-(2-chloro-3,6-difluoro-benzyloxy)-[3,3′]bipyridinyl-6,6′-diamine;5′-(2,6-dichloro-benzyloxy)-[2,3′]bipyridinyl-6′-ylamine;5-(2,6-dichloro-benzyloxy)-[3,3′]bipyridinyl-6-ylamine;5-(2,6-dichloro-benzyloxy)-[3,4′]bipyridinyl-6-ylamine;3-(2,6-dichloro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine;5-(2,6-dichloro-benzyloxy)-[3,3′]bipyridinyl-6,6′-diamine;5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6,6′-diamine;{6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-4-yl}-(4-methyl-piperazin-1-yl)-methanone;{6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-6-yl}-(4-methyl-piperazin-1-yl)-methanone;{6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-5-yl}-(4-methyl-piperazin-1-yl)-methanone;{6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-yl}-(4-methyl-piperazin-1-yl)-methanone;{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,4′]bipyridinyl-2′-yl}-(4-methyl-piperazin-1-yl)-methanone;5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6,6′-diamine;{6′-amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-5-yl}-(4-methyl-piperazin-1-yl)-methanone;{6′-amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-4-yl)-methanone;{6′-amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-6-yl}-(4-methyl-piperazin-1-yl)-methanone;{6′-amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-5-yl}-(4-methyl-piperazin-1-yl)-methanone;{6′-amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-yl}-(4-methyl-piperazin-1-yl)-methanone;{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,4′]bipyridinyl-2′-yl}-(4-methyl-piperazin-1-yl)-methanone;5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-6′-ylamine;5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-6′-ylamine;5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-pyrimidin-5-yl-pyridin-2-ylamine;{6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-5-yl}-(4-methyl-piperazin-1-yl)-methanone;5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,4′]bipyridinyl-6-ylamine;5-benzyloxy-3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-2-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-(2-ethyl-butoxy)-pyridin-2-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-(3-methyl-butoxy)-pyridin-2-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-butoxy-pyridin-2-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-propoxy-pyridin-2-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-cyclohexylmethoxy-pyridin-2-ylamine;6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-ol;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-(2-cyclohexyl-ethoxy)-pyridin-2-ylamine;3-[-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-isobutoxy-pyridin-2-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-phenethyloxy-pyridin-2-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-(pyridin-2-ylmethoxy)-pyridin-2-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-(pyridin-4-ylmethoxy)-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;5-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-fluoro-benzonitrile;4-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-piperidin-4-ol;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-piperidin-1-yl-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-pyrrolidin-1-yl-methanone;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-3-methyl-benzoicacid methyl ester;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(dimethyl-piperazin-1-ylmethyl)-phenyl]-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-3,5-dimethoxy-phenyl)-(dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-fluoro-phenyl)-(dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-3-fluoro-phenyl)-(dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-3-methyl-phenyl)-(dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-[1,4]diazepan-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-[1,4]diazepan-1-yl-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-piperazin-1-yl-methanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-vinyl-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,4S)-3,4-dihydroxy-pyrrolidin-1-yl)-methanone;5-[(1-benzyl-pyrrolidin-3-ylamino)-methyl]-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-N-azetidin-3-yl-benzamide;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-N,N-dimethyl-benzenesulfonamide;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(6-methoxy-1H-benzoimidazol-2-yl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(6-methoxy-1-methyl-1H-benzoimidazol-2-yl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(4-methyl-[1,4]diazepane-1-sulfonyl)-phenyl]-pyridin-2-ylamine;6-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1-methyl-1H-indazole-3-carboxylicacid amide;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-methyl-1H-pyrazol-4-yl)-pyridin-2-ylamine;5-(3-chloro-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-fluoro-3-methyl-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-fluoro-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-trifluoromethoxy-phenyl)-pyridin-2-ylamine;5-benzo[1,3]dioxol-5-yl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)phenol;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanol;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzonitrile;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-methoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-dichloro-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,5-dimethyl-phenyl)-pyridin-2-ylamine;5-(5-chloro-2-methoxy-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;5-(3-chloro-4-fluoro-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(5-fluoro-2-methoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-isopropyl-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-dichloro-phenyl)-pyridin-2-ylamine;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzonitrile;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-difluoro-phenyl)-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-methanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-ethoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,5-dimethoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,4-dimethoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,6-dimethoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine;5-(2-chloro-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-trifluoromethoxy-phenyl)-pyridin-2-ylamine;1-(2-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-ethanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-fluoro-phenyl)-pyridin-2-ylamine;(2-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanol;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-o-tolyl-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-methoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,6-dimethyl-phenyl)-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-morpholin-4-yl-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-chloro-phenyl)-((3R,5S)-dimethyl-piperazin-1-yl)-methanone;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)}-2-methyl-phenyl)-((3R,5S)-dimethyl-piperazin-1-yl)-methanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-((2R,6S)-2,6-dimethyl-morpholin-4-ylmethyl)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-morpholin-4-ylmethyl-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-dimethyl-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-m-tolyl-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-dimethoxy-phenyl)-pyridin-2-ylamine;5-biphenyl-3-yl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;5-(3,5-bis-trifluoromethyl-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-dichloro-phenyl)-pyridin-2-ylamine;1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-ethanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-difluoro-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,5-dichloro-phenyl)-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-4-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-ethoxy-phenyl)-pyridin-2-ylamine;(4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(3-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone;7-[4-(3,5-dimethyl-piperazine-1-carbonyl)-phenyl]-2-phenyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;{4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone;{4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone;[4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenyl]-(3,5-dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-ethyl-piperazin-1-yl)-methanone;[4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenyl]-(4-ethyl-piperazin-1-yl)-methanone;{4-[6-amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone;3-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzoicacid methyl ester;3-{2-amino-5-[4-(3,5-dimethyl-piperazine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzoicacid methyl ester;{4-[6-amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;[4-(6-amino-5-cyclohexylmethoxy-pyridin-3-yl)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;4-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-[2-(3-hydroxy-phenyl)-ethyl]-benzamide;4-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-[2-(2,6-dichloro-phenyl)-ethyl]-benzamide;4-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-(1-benzyl-piperidin-4-yl)-benzamide;4-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-ethyl-piperazin-1-yl)-methanone;{4[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone;(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanone;5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-6′-(2-morpholin-4-yl-ethoxy)-[3,3′]bipyridinyl-6-ylamine;6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-1-(2-pyrrolidin-1-yl-ethyl)-1H-[3,3′]bipyridinyl-6-one;5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-6′-(2-pyrrolidin-1-yl-ethoxy)-[3,3′]bipyridinyl-6-ylamine;6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-[3,3′]bipyridinyl-6-one;(4-{6-amino-5-[1-(2,4,6-trimethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;(4-{6-amino-5-[1-(2-chloro-6-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-fluoro-phenyl)-pyridin-2-ylamine;6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-1H-[3,3′]bipyridinyl-6-one;5′-bromo-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-dimethylamino-phenyl)-pyridin-2-ylamine;5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-2′-methoxy-[3,3′]bipyridinyl-6-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-indol-5-yl)-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-propoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone;[4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;3-(2,6-dichloro-3-fluoro-benzyloxy)-5-thiazol-2-yl-pyridin-2-ylamine;(4-(6-amino-5-[1-(2-fluoro-6-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;3-(2,6-dichloro-3-fluoro-benzyloxy)-5-(1-methyl-1H-imidazol-2-yl)-pyridin-2-ylamine;{4-[6-amino-5-(2,4,6-trimethyl-benzyloxy)-pyridin-3-yl]-phenyl)(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;(4-[6-amino-5-(2,3,5,6-tetramethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;{4-[6-amino-5-(2,4,6-trifluoro-benzyloxy)-pyridin-3-yl]-phenyl)(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;(4-{6-amino-5-[1-(2-fluoro-6-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-N-methyl-nicotinamidine;6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-N-(2-morpholin-4-yl-ethyl)-nicotinamidine;(4-{6-amino-5-[1-(2,4,5-trifluoro-phenyl)-propoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;(4-{6-amino-5-[1-(6-chloro-2-fluoro-3-methyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;3-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy)ethyl)-benzoicacid; and pharmaceutically acceptable salts, hydrates and solvatesthereof.

In another embodiment, the invention provides a compound selected fromthe group consisting of:3-{5-amino-6-[-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl)-N-(1-methyl-piperidin-4-yl)-benzamide;3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl)-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzamide;{3-(5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;(3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;(3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone;(3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone;4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid;4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yphenyl)-(4-pyrrolidin-1-yl)-methanone;4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone;4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl)benzamide;2-[4-(2-Hydroxy-acetyl)-piperazin-1-yl]-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;3-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzoicacid;{3-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;3-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-N-{2-[ethyl-(2-methoxy-ethyl)-amino]-ethyl}-benzamide;{3-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;3-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-N-(3-pyrrolidin-1-yl-propyl)-benzamide;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzamide;{4-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;{4-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone;{4-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-phenyl}-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-morpholin-4-yl-propyl)-benzamide;(3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylphenyl}-(4-cyclopropylamino-piperidin-1-yl)-methanone;3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((S)-2-hydroxy-3-morpholin-4-yl-propyl)-benzamide;3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((R)-2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;2-diethylamino-ethanesulfonic acid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;2-dimethylamino-ethanesulfonic acid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;2-((R)-3-Hydroxy-pyrrolidin-1-yl)-ethanesulfonic acid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;2-pyrrolidin-1-yl)-ethanesulfonic acid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}phenyl)-amide;4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid;4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}N-((R)-2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide;(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-cyclopropylamino-piperidin-1-yl)-methanone;4{-5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((S)-2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide;4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((R)-2-hydroxy-3-morpholin-4-yl-propyl)-benzamide;4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid;(4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;(4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;(4-(5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(4-(5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-3-aminopyrrolidin-1-yl)-methanone;(4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-3-aminopyrrolidin-1-yl)-methanonehydrogen chloride;4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid;3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;(3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;(3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-benzamide;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-benzamide;(3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;(3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone;(3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanonehydrochloride salt;(3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;1-(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea;(R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;1-(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea;4-methyl-piperazine-1-carboxylic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;1-(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-3-(2-hydroxy-ethyl)-urea;(S)-3-amino-pyrrolidine-1-carboxylic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;1-(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-3-(1-methyl-piperidin-4-yl)-urea;4-methyl-piperazine-1-carboxylic acid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl)-phenyl)-amide;1-(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl)-phenyl)-3-(2-hydroxy-ethyl)-urea; (S)-3-amino-pyrrolidine-1-carboxylicacid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide;1-(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl-phenyl}-3-(1-methyl-piperidin-4-yl)-urea;5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophene-2-carboxylicacid;{5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophen-2-yl}-(4-methyl-piperazin-1-yl)-methanone;{5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophen-2-yl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;{5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophen-2-yl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;(5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophen-2-yl}-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;5-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophene-2-carboxylicacid (2-morpholin-4-yl-ethyl)-amide;3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-pyrazin-2-aminetrifluoroacetate;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-pyridin-4-yl-pyrazin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-pyrrol-2-yl}-pyrazin-2-ylamine;(6-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone;(2-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-4-yl)-(4-methyl-piperazin-1-yl)-methanone;(6-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone;(5-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone;(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl)pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone;6-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-nicotinamide;5-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-nicotinamide;6-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-morpholin-4-yl-propyl)-nicotinamide;5-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-morpholin-4-yl-propyl)-nicotinamide;(6-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-3-yl)-(4-isopropyl-piperazin-1-yl)-methanone;and pharmaceutically acceptable salts, hydrates and solvates thereof.

In another aspect, the invention provides a compound selected from thegroup consisting of the compounds shown in Table 1 and pharmaceuticallyacceptable salts, hydrates and solvates thereof.

In another aspect, the invention provides a compound selected from thegroup consisting of the compounds shown in Table 2 and pharmaceuticallyacceptable salts, hydrates and solvates thereof.

In another aspect, the invention provides a compound selected from thegroup consisting of the compounds shown in Table 3 and pharmaceuticallyacceptable salts, hydrates and solvates thereof.

In another aspect, the invention provides a compound selected from thegroup consisting of the compounds shown in Table 4 and pharmaceuticallyacceptable salts, hydrates and solvates thereof.

In another aspect, the invention provides a compound selected from thegroup consisting of the compounds shown in Table 5 and pharmaceuticallyacceptable salts, hydrates and solvates thereof.

In another aspect, the invention provides a compound selected from thegroup consisting of the compounds shown in Table 6 and pharmaceuticallyacceptable salts, hydrates and solvates thereof.

In another aspect, the invention provides a compound selected from thegroup consisting of the compounds shown in Table 7 and pharmaceuticallyacceptable salts, hydrates and solvates thereof.

In another aspect, the invention provides a compound selected from thegroup consisting of the compounds shown in Table 8 and pharmaceuticallyacceptable salts, hydrates and solvates thereof.

In another embodiment, the invention provides compounds having thefollowing chemical structure (Formula 6):

wherein,

Z is CH or N;

Aryl is an optionally fused aryl or an optionally fused heteroaryl groupwhich is optionally substituted by one or more substituents selectedfrom the group consisting of a halogen, —OR²⁴, —COR²⁴, —COOR²⁴,—CONR²⁴R²⁵, —CN, —NO₂, —S(O)_(m)R²⁴, —SO₂NR²⁴R²⁵, perfluoroalkyl, loweralkyl, cycloalkyl, heterocycle, alkenyl, alkynyl, aryl, —NR²⁴R²⁵,—NR²⁴C(O)R²⁵ and —NR²⁴S(O)_(p)R^(25;)

R²¹ and R²² are independently selected from the group consisting ofhydrogen, halogen, —COR²⁴, —COOR²⁴, —CONR²⁴R²⁵, —CN, perfluoroalkyl,lower alkyl, cycloalkyl, heterocycle, alkenyl, alkynyl, and aryl;

R²³ is selected from the group consisting of:

an optionally fused aryl, heteroaryl, alicyclic or heterocyclic group,optionally substituted by one or more substituents selected from thegroup consisting of a halogen, —(CH₂)_(n)—OR²⁴, —COR²⁴, —COOR²⁴,—CONR²⁴R, —CN, —NO₂, —S(O)_(m)R, —SO₂NR²⁴R²⁵, perfluoroalkyl,—O-perfluoroalkyl, lower alkyl, cycloalkyl, heterocycle, heteroaryl,alkenyl, alkynyl, aryl, —(CH₂), —NR²⁴R²⁵, —NR²⁴C(O)R²⁵ and—NR²⁴S(O)_(p)R²⁵, wherein said heterocycle, heteroaryl and arylsubstituents may be optionally substituted by a group selected from thegroup consisting of lower alkyl, halogen, —C(O)NR⁴R², NR²⁴R²,NR²⁴C(O)R²⁵ and NR²⁴S(O)_(p)R²⁵;

—OR²⁴, —COR²⁴, —COOR²⁴, —CN, —NO₂, —S(O)_(m)R²⁴, —SO₂NR²⁴R²⁵,perfluoroalkyl, cycloalkyl, heterocycle, alkenyl, and alkynyl;

R²⁴ and R²⁵ are independently selected from the group consisting ofhydrogen, lower alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aminoalkyl,alkylaminoalkyl, alkylaminocycloalkyl, dialkylaminoalkyl and—(CH₂)_(n)-heterocycle, wherein said —(CH₂)_(n)-heterocycle may befurther substituted by one or more of lower alkyl, —(CH₂)_(n)-hydroxy,heterocycle and —C(O)R²⁶,

or R²⁴ and R²⁵ can combine to form a 5- to 6-membered heterocyclic ringhaving one or more heteroatoms selected from the group consisting of N,O, S, S(O) and SO₂, said 5- to 6-membered heterocyclic ring may beoptionally substituted by lower alkyl, —(CH₂)_(n)-heterocycle,cycloalkyl, halo, —(CH₂)_(n)—N R²R²⁷, amino, —C(O)R²⁶, —NR²⁶—C(O)OR²7and —NR²⁶—C(O)R²⁷;

wherein R²⁶ and R²⁷ are independently selected from the group consistingof hydrogen, lower alkyl, —(CH₂)_(n)-cycloalkyl and —C(O)—(CH₂), —OH;

except that when Z is N and R²¹ and R²² are H and Aryl ism-chlorophenyl, R²³ is not piperazine;

m is 0, 1 or 2;

n is 0, 1, 2 or 3;

p is 1 or 2;

or a pharmaceutically acceptable salt thereof.

In preferred aspect of this embodiment, in the compound of Formula (6),R²³ is aryl or heteroaryl.

In another preferred aspect of this embodiment, when Z is N, R²³ is notheteroalicyclic.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising any of the inventive compounds described herein.In particular aspects of this embodiment, the pharmaceutical compositioncomprises a compound of formula 1, a compound of formula 2, a compoundof formula 3, a compound of formula 4, a compound of formula 5, acompound of formula 6, or a pharmaceutically acceptable salt, hydrate orsolvate thereof, including particular aspects thereof as describedabove. In other particular aspects of this embodiment, thepharmaceutical composition comprises a compound selected from thecompounds shown in Table 1, a compound selected from the compounds shownin Table 2, a compound selected from the compounds shown in Table 3, acompound selected from the compounds shown in Table 4, a compoundselected from the compounds shown in Table 5, a compound selected fromthe compounds shown in Table 6, a compound selected from the compoundsshown in Table 7, a compound selected from the compounds shown in Table8, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Preferred compounds of the invention include those having c-METinhibitory activity as defined by any one or more of IC₅₀, Ki, orpercent inhibition. One skilled in the art can readily determine if acompound has such activity by carrying out the appropriate assay. In oneembodiment, particularly preferred compounds have a c-MET IC₅₀ of lessthan 5 μM, or less than 2 μM, or less than 1 μM, or less than 500 nM, orless than 400 nM, or less than 300 nM, or less than 200 nM, or less than100 nM, or less than 50 nM. In another embodiment, particularlypreferred compounds have a c-MET Ki of less than 5 μM or less than 2 μM,or less than 1 μM, or less than 500 nM, or less than 400 nM, or lessthan 300 nM, or less than 200 nM, or less than 100 nM, or less than 50nM. In another embodiment, particularly preferred compounds have a c-METinhibition at 1 μM of at least 10% or at least 20% or at least 30% or atleast 40% or at least 50% or at least 60% or at least 70% or at least80% or at least 90%.

In another embodiment, the invention provides a process of preparing thecompound of Formula (6), comprising

(i) brominating a compound of the formula (a):

to give a compound of formula (b):

and

ii. reacting (b) with a boronic acid or ester derivative of the formulaR²³B(OR)₂ in the presence of a palladium catalyst;

wherein R is hydrogen or an alcohol protecting group and Aryl, R²¹, R²²,and R²³ are as defined defined above.

In another embodiment, R²³ is aryl or heteroaryl.

In another embodiment the invention provides a method of treating asubject suffering from a condition for which inhibition of Met receptortyrosine kinase is indicated, comprising administering to the subject atherapeutically effective amount of any of the inventive compoundsdescribed herein.

The chemical formulae referred to herein may exhibit the phenomena oftautomerism and structural isomerism. This invention encompasses anytautomeric or structural isomeric form and mixtures thereof whichpossess the ability to modulate RTK, CTK and/or STK activity and is notlimited to any one tautomeric or structural isomeric form.

In addition, the formulae referred to herein may also exhibitstereoisomerism, in which such compounds may adopt an R or Sconfiguration at chiral centers. Thus, this invention also encompassesany stereoisomeric form, their corresponding enantiomers (d- and I- or(+) and (−) isomers) and diastereomers thereof, and mixtures thereof,which possess the ability to modulate RTK, CTK and/or STK activity andis not limited to any one stereoisomeric form.

In particular embodiments, the compound is chosen from the compounds inTables 1–8.

Another embodiment of the invention relates to a method of treating asubject suffering from a condition for which inhibition of proteinkinase is indicated, comprising administering to the subject atherapeutically effective amount of any of the inventive compoundsdescribed herein.

Another aspect of this invention relates to a method for the modulationof the catalytic activity of a PK by contacting a PK with a compound ofthis invention or a physiologically acceptable salt thereof.

A further aspect of this invention is that the modulation of thecatalytic activity of PKs using a compound of this invention may becarried out in vitro or in vivo.

A still further aspect of this invention is that the protein kinasewhose catalytic activity is being modulated by a compound of thisinvention is selected from the group consisting of receptor proteintyrosine kinases, cellular tyrosine kinases and serine-threoninekinases.

It is an aspect of this invention that the receptor tyrosine proteinkinase whose catalytic activity is modulated by a compound of thisinvention is selected from the group consisting of EGF, HER2, HER3,HER4, IR, IGF-1R, IRR, PDGFRα, PDGFRβ, CSFIR, C-Kit, C-fms, Flk-1R,Flk-4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R, FGFR-4R, MET, DDR-1and DDR-2.

In addition, it is an aspect of this invention that the cellulartyrosine kinase whose catalytic activity is modulated by a compound ofthis invention is selected from the group consisting of Src, Frk, Btk,Csk, Abl, ZAP70, Fes/Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck,Fgr and Yrk.

Another aspect of this invention is that the serine-threonine proteinkinase whose catalytic activity is modulated by a compound of thisinvention is selected from the group consisting of CDK2, Raf, NEK andBUB1.

Another aspect of this invention relates to a method for treating orpreventing a protein kinase related disorder in an organism comprisingadministering a therapeutically effective amount of any of the inventivecompounds described herein to an organism, such as a mammal,particularly a human.

It is an aspect of this invention that the above-referenced proteinkinase related disorder is selected from the group consisting of areceptor protein tyrosine kinase related disorder, a cellular tyrosinekinase disorder and a serine-threonine kinase related disorder.

In yet another aspect of this invention, the above referenced proteinkinase related disorder is selected from the group consisting of a Metrelated disorder, an AUR² related disorder, a ZC1 related disorder, aPDGFR related disorder, an IGFR related disorder and a flk relateddisorder.

The above referenced protein kinase related disorders include by way ofexample and not limitation, cancers such as lung cancer, NSCLC (nonsmall cell lung cancer), bone cancer, pancreatic cancer, skin cancer,cancer of the head and neck, cutaneous or intraocular melanoma, uterinecancer, ovarian cancer, rectal cancer, cancer of the anal region,stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g.,uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of theendometrium, carcinoma of the cervix, carcinoma of the vagina orcarcinoma of the vulva), Hodgkin's Disease, cancer of the esophagus,cancer of the small intestine, cancer of the endocrine system (e.g.,cancer of the thyroid, parathyroid or adrenal glands), sarcomas of softtissues, cancer of the urethra, cancer of the penis, prostate cancer,chronic or acute leukemia, solid tumors of childhood, lymphocyticlymphomas, cancer of the bladder, cancer of the kidney or ureter (e.g.,renal cell carcinoma, carcinoma of the renal pelvis), pediatricmalignancy, neoplasms of the central nervous system (e.g., primary CNSlymphoma, spinal axis tumors, brain stem glioma or pituitary adenomas),cancers of the blood such as acute myeloid leukemia, chronic mueloidleukemia, etc, Barrett's esophagus (pre-malignant syndrome), neoplasticcutaneous disease, psoriasis, mycoses fungoides and benign prostatichypertrophy, diabetes related diseases such as diabetic retinopathy,retinal ischemia and retinal neovascularization, hepatic cirrhosis,cardiovascular disease such as atherosclerosis, immunological diseasesuch as autoimmune disease and renal disease. Preferably, the disease iscancer such as acute myeloid leukemia and colorectal cancer.

The above referenced protein kinase related disorder also includesdisorders selected from the group consisting of diabetes, ahyper-proliferation disorder, hyperproliferative disorders of thekidney, von Hippel-Lindau disease, restenosis, fibrosis, psoriasis,osteoarthritis, rheumatoid arthritis, an inflammatory disorder andangiogenesis in yet another aspect of this invention.

Additional disorders which may be treated or prevented using thecompounds of this invention are immunological disorders such asautoimmune diseases (e.g., AIDS, lupus, etc.) and cardiovasculardisorders such as atherosclerosis.

It is an aspect of this invention that the protein kinase relateddisorder being treated or prevented by administration of a compound ofthis invention is a met kinase related disorder.

The organism in which the protein kinase related disorder is beingtreated or prevented is a human being in yet another aspect of thisinvention.

It is also an aspect of this invention that a compound described herein,or its salt, might be combined with other chemotherapeutic agents forthe treatment of the diseases and disorders discussed above. Forinstance, a compound or salt of this invention might be combined withalkylating agents such as fluorouracil (5-FU) alone or in furthercombination with leukovorin; or other alkylating agents such as, withoutlimitation, other pyrimidine analogs such as UFT, capecitabine,gemcitabine and cytarabine, the alkyl sulfonates, e.g., busulfan (usedin the treatment of chronic granulocytic leukemia), improsulfan andpiposulfan; aziridines, e.g., benzodepa, carboquone, meturedepa anduredepa; ethyleneimines and methylmelamines, e.g., altretamine,triethylenemelamine, triethylenephosphoramide,trethylenethiophosphoramide and trimethylolmelamine; and the nitrogenmustards, e.g., chlorambucil (used in the treatment of chroniclymphocytic leukemia, primary macroglobulinemia and non-Hodgkin'slymphoma), cyclophosphamide (used in the treatment of Hodgkin's disease,multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lungcancer, Wilm's tumor and rhabdomyosarcoma), estramustine, ifosfamide,novembrichin, prednimustine and uracil mustard (used in the treatment ofprimary thrombocytosis, non-Hodgkin's lymphoma, Hodgkin's disease andovarian cancer); and triazines, e.g., dacarbazine (used in the treatmentof soft tissue sarcoma).

Likewise a compound or salt of this invention might be expected to havea beneficial effect in combination with other antimetabolitechemotherapeutic agents such as, without limitation, folic acid analogs,e.g. methotrexate (used in the treatment of acute lymphocytic leukemia,choriocarcinoma, mycosis fungiodes breast cancer, head and neck cancerand osteogenic sarcoma) and pteropterin; and the purine analogs such asmercaptopurine and thioguanine which find use in the treatment of acutegranulocytic, acute lymphocytic and chronic granulocytic leukemias.

A compound or salt of this invention might also be expected to proveefficacious in combination with natural product based chemotherapeuticagents such as, without limitation, the vinca alkaloids, e.g.,vinblastin (used in the treatment of breast and testicular cancer),vincristine and vindesine; the epipodophylotoxins, e.g., etoposide andteniposide, both of which are useful in the treatment of testicularcancer and Kaposi's sarcoma; the antibiotic chemotherapeutic agents,e.g., daunorubicin, doxorubicin, epirubicin, mitomycin (used to treatstomach, cervix, colon, breast, bladder and pancreatic cancer),dactinomycin, temozolomide, plicamycin, bleomycin (used in the treatmentof skin, esophagus and genitourinary tract cancer); and the enzymaticchemotherapeutic agents such as L-asparaginase.

In addition to the above, a compound or salt of this invention might beexpected to have a beneficial effect used in combination with theplatinum coordination complexes (cisplatin, etc.); substituted ureassuch as hydroxyurea; methylhydrazine derivatives, e.g., procarbazine;adrenocortical suppressants, e.g., mitotane, aminoglutethimide; andhormone and hormone antagonists such as the adrenocorticosteriods (e.g.,prednisone), progestins (e.g., hydroxyprogesterone caproate); estrogens(e.g., diethylstilbesterol); antiestrogens such as tamoxifen; androgens,e.g., testosterone propionate; and aromatase inhibitors (such asanastrozole.

Finally, the combination of a compound of this invention might beexpected to be particularly effective in combination with mitoxantroneor paclitaxel for the treatment of solid tumor cancers or leukemias suchas, without limitation, acute myelogenous (non-lymphocytic) leukemia.

The above method can be carried out in combination with achemotherapeutic agent selected from the group consisting of mitoticinhibitors, alkylating agents, antimetabolites, cell cycle inhibitors,enzymes, topoisomerase inhibitors, biological response modifiers,anti-hormones, antiangiogenic agents such as MMP-2, MMP-9 and COX-2inhibitors, and anti-androgens.

Examples of useful COX-II inhibitors include VIOXX™, CELEBREX™(alecoxib), valdecoxib, paracoxib, rofecoxib, and Cox 189. Examples ofuseful matrix metalloproteinase inhibitors are described in WO 96/33172(published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996),European Patent Application No. 97304971.1 (filed Jul. 8, 1997),European Patent Application No. 99308617.2 (filed Oct. 29, 1999), WO98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan. 29,1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915 (publishedAug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO 98/30566(published Jul. 16, 1998), European Patent Publication 606,046(published Jul. 13, 1994), European Patent Publication 931,788(published Jul. 28, 1999), WO 90/05719 (published May 31, 1990), WO99/52910 (published Oct. 21, 1999), WO 99/52889 (published Oct. 21,1999), WO 99/29667 (published Jun. 17, 1999), PCT InternationalApplication No. PCT/IB98/01113 (filed Jul. 21, 1998), European PatentApplication No. 99302232.1 (filed Mar. 25, 1999), Great Britain patentapplication number 9912961.1 (filed Jun. 3, 1999), U.S. ProvisionalApplication No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat. No.5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued Jan.19, 1999), and European Patent Publication 780,386 (published Jun. 25,1997), all of which are incorporated herein in their entireties byreference. Preferred MMP-2 and MMP-9 inhibitors are those that havelittle or no activity inhibiting MMP-1. More preferred, are those thatselectively inhibit MMP-2 and/or MMP-9 relative to the othermatrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in the present inventionare AG-3340, RO 32-3555, RS 13-0830, and the compounds recited in thefollowing list:

3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionicacid;3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylicacid hydroxyamide; (2R, 3R)1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylicacid hydroxyamide;4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylicacid hydroxyamide;3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionicacid;4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylicacid hydroxyamide; (R)3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylicacid hydroxyamide; (2R,3R)1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylicacid hydroxyamide;3-[[(4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionicacid;3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionicacid;3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylicacid hydroxyamide;3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylicacid hydroxyamide; and (R)3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylicacid hydroxyamide; and pharmaceutically acceptable salts and solvates ofsaid compounds.

Other anti-angiogenesis agents, including other COX-II inhibitors andother MMP inhibitors, can also be used in the present invention.

A compound of the invention can also be used with signal transductioninhibitors, such as agents that can inhibit EGFR (epidermal growthfactor receptor) responses, such as EGFR antibodies, EGF antibodies, andmolecules that are EGFR inhibitors; VEGF (vascular endothelial growthfactor) inhibitors; and erbB2 receptor inhibitors, such as organicmolecules or antibodies that bind to the erbB2 receptor, for example,HERCEPTINΘ (Genentech, Inc. of South San Francisco, Calif., USA). EGFRinhibitors are described in, for example in WO 95/19970 (published Jul.27, 1995), WO 98/14451 (published Apr. 9, 1998), WO 98/02434 (publishedJan. 22, 1998), and U.S. Pat. No. 5,747,498 (issued May 5, 1998), andsuch substances can be used in the present invention as describedherein.

EGFR-inhibiting agents include, but are not limited to, the monoclonalantibodies C225 and anti-EGFR 22Mab (ImClone Systems Incorporated of NewYork, N.Y., USA), the compounds ZD-1839 (AstraZeneca), BIBX-1382(Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, N.J., USA),and OLX-103 (Merck & Co. of Whitehouse Station, N.J., USA), VRCTC-310(Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton,Mass.).

These and other EGFR-inhibiting agents can be used in the presentinvention.

VEGF inhibitors, for example3-(2,4-Dimethylpyrrol-5-yl)methylene-2-indolinone,5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylicacid (2-diethylamino-ethyl)-amide,3-[2,4-dimethyl-5-oxo-1,2-dihydroindole-3-ylidenemethyl)-1H-pyrrol-3-yl-propionicacid (Sugen Inc. of South San Francisco, Calif., USA), can also becombined with an inventive compound described herein. VEGF inhibitorsare described in, for example in WO 99/24440, PCT InternationalApplication PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613, WO99/61422 (published Dec. 2, 1999), U.S. Pat. No. 5,834,504 (issued Nov.10, 1998), WO 01/60814,WO 02/04407, WO 98/50356, U.S. Pat. No. 5,883,113(issued Mar. 16, 1999), U.S. Pat. No. 5,886,020 (issued Mar. 23, 1999),U.S. Pat. No. 5,792,783 (issued Aug. 11, 1998), WO 99/10349 (publishedMar. 4, 1999), WO 97/32856 (published Sep. 12, 1997), WO 97/22596(published Jun. 26, 1997), WO 98/54093 (published Dec. 3, 1998), WO98/02438 (published Jan. 22, 1998), WO 99/16755 (published Apr. 8,1999), and WO 98/02437 (published Jan. 22, 1998), all of which areincorporated herein in their entireties by reference. Other examples ofsome specific VEGF inhibitors useful in the present invention are IM862(Cytran Inc. of Kirkland, Wash., USA); anti-VEGF monoclonal antibody ofGenentech, Inc. of South San Francisco, Calif.; and angiozyme, asynthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron(Emeryville, Calif.). These and other VEGF inhibitors can be used in thepresent invention as described herein.

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc), andthe monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. ofTheWoodlands, Tex., USA) and 2B-1 (Chiron), can furthermore be combinedwith a compound any of the inventive compounds described herein, forexample those indicated in WO 98/02434 (published Jan. 22, 1998), WO99/35146 (published Jul. 15, 1999), WO 99/35132 (published Jul. 15,1999), WO 98/02437 (published Jan. 22, 1998), WO 97/13760 (publishedApr. 17, 1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No.5,587,458 (issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issuedMar. 2, 1999), which are all hereby incorporated herein in theirentireties by reference. ErbB2 receptor inhibitors useful in the presentinvention are also described in U.S. Provisional Application No.60/117,341, filed Jan. 27, 1999, and in U.S. Provisional Application No.60/117,346, filed Jan. 27, 1999, both of which are incorporated in theirentireties herein by reference. The erbB2 receptor inhibitor compoundsand substance described in the aforementioned PCT applications, U.S.patents, and U.S. provisional applications, as well as other compoundsand substances that inhibit the erbB2 receptor, can be used with theinventive compounds described herein.

The inventive compounds described herein can also be used with otheragents useful in treating cancer, including, but not limited to, agentscapable of enhancing antitumor immune responses, such as CTLA4(cytotoxic lymphocite antigen 4) antibodies, and other agents capable ofblocking CTLA4; and anti-proliferative agents such as other farnesylprotein transferase inhibitors, for example the farnesyl proteintransferase inhibitors described in the references cited in the“Background” section, of U.S. Pat. No. 6,258,824 B1. Specific CTLA4antibodies that can be used in the present invention include thosedescribed in U.S. Provisional Application 60/113,647 (filed Dec. 23,1998) which is incorporated by reference in its entirety, however otherCTLA4 antibodies can be used in the present invention.

The above method can be also be carried out in combination withradiation therapy, wherein the amount of the inventive compound incombination with the radiation therapy is effective in treating theabove diseases. Techniques for administering radiation therapy are knownin the art, and these techniques can be used in the combination therapydescribed herein. The administration of the compound of the invention inthis combination therapy can be determined as described herein.

Another aspect of the invention is directed to the use of any of theinventive compounds described herein in the preparation of a medicament,which is useful in the treatment of a disease mediated by abnormal Metkinase activity, such as cancer.

DETAILED DESCRIPTION

Definitions

The terms pyridine and pyrazine refer to the following structuresrespectively:

“Pharmaceutically acceptable salt” or “pharmaceutically acceptable saltthereof” refer to those salts which retain the biological effectivenessand properties of the free bases and which are obtained by reaction withinorganic or organic acids, such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, ρ-toluenesulfonic acid,salicylic acid, acetic acid, benzenesulfonic acid (besylate), benzoicacid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid,glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid,mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid,tartaric acid, and the like.

A “pharmaceutical composition” refers to a mixture of one or more of thecompounds described herein, or physiologically acceptable salts thereof,with other chemical components, such as physiologically acceptablecarriers and excipients. The purpose of a pharmaceutical composition isto facilitate administration of a compound to an organism.

As used herein, a “physiologically acceptable carrier” refers to acarrier or diluent that does not cause significant irritation to anorganism and does not abrogate the biological activity and properties ofthe administered compound.

An “excipient” refers to an inert substance added to a pharmaceuticalcomposition to further facilitate administration of a compound.Examples, without limitation, of excipients include calcium carbonate,calcium phosphate, various sugars and types of starch, cellulosederivatives (including microcrystalline cellulose), gelatin, vegetableoils, polyethylene glycols, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or arrangements of their atoms inspace are termed “isomers.” Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition J. March, John Wiley and Sons, New York, 1992).

The inventive compounds herein may exhibit the phenomena of tautomerismand structural isomerism. This invention encompasses any tautomeric orstructural isomeric form and mixtures thereof which possess the abilityto modulate RTK, CTK and/or STK activity and is not limited to any onetautomeric or structural isomeric form.

It is contemplated that an inventive compound as described herein wouldbe metabolized by enzymes in the body of the organism such as humanbeing to generate a metabolite that can modulate the activity of theprotein kinases. Such metabolites are within the scope of the presentinvention.

As used herein, “PK” refers to receptor protein tyrosine kinase (RTKs),non-receptor or “cellular” tyrosine kinase (CTKs) and serine-threoninekinases (STKs).

The term “method” refers to manners, means, techniques and proceduresfor accomplishing a given task including, but not limited to, thosemanners, means, techniques and procedures either known to, or readilydeveloped from known manners, means, techniques and procedures by,practitioners of the chemical, pharmaceutical, biological, biochemicaland medical arts.

As used herein, the term “modulation” or “modulating” refers to thealteration of the catalytic activity of RTKs, CTKs and STKs. Inparticular, modulating refers to the activation of the catalyticactivity of RTKs, CTKs and STKs, preferably the activation or inhibitionof the catalytic activity of RTKs, CTKs and STKs, depending on theconcentration of the compound or salt to which the RTK, CTK or STK isexposed or, more preferably, the inhibition of the catalytic activity ofRTKs, CTKs and STKs.

The term “catalytic activity” as used herein refers to the rate ofphosphorylation of tyrosine under the influence, direct or indirect, ofRTKs and/or CTKs or the phosphorylation of serine and threonine underthe influence, direct or indirect, of STKs.

The term “contacting” as used herein refers to bringing a compound ofthis invention and a target PK together in such a manner that thecompound can affect the catalytic activity of the PK, either directly,i.e., by interacting with the kinase itself, or indirectly, i.e., byinteracting with another molecule on which the catalytic activity of thekinase is dependent. Such “contacting” can be accomplished in vitro,i.e., in a test tube, a petri dish or the like. In a test tube,contacting may involve only a compound and a PK of interest or it mayinvolve whole cells. Cells may also be maintained or grown in cellculture dishes and contacted with a compound in that environment. Inthis context, the ability of a particular compound to affect a PKrelated disorder, i.e., the IC₅₀ of the compound, defined below, can bedetermined before use of the compounds in vivo with more complex livingorganisms is attempted. For cells outside the organism, multiple methodsexist, and are well-known to those skilled in the art, to get the PKs incontact with the compounds including, but not limited to, direct cellmicroinjection and numerous transmembrane carrier techniques.

“In vitro” refers to procedures performed in an artificial environmentsuch as, e.g., without limitation, in a test tube or culture medium. Theskilled artisan will understand that, for example, an isolated PK may becontacted with a modulator in an in vitro environment. Alternatively, anisolated cell may be contacted with a modulator in an in vitroenvironment.

As used herein, “in vivo” refers to procedures performed within a livingorganism such as, without limitation, a mouse, rat, rabbit, ungulate,bovine, equine, porcine, canine, feline, primate, or human.

As used herein, “PK related disorder,” “PK driven disorder,” and“abnormal PK activity” all refer to a condition characterized byinappropriate, i.e., under or, more commonly, over, PK catalyticactivity, where the particular PK can be an RTK, a CTK or an STK.Inappropriate catalytic activity can arise as the result of either: (1)PK expression in cells which normally do not express PKs, (2) increasedPK expression leading to unwanted cell proliferation, differentiationand/or growth, or, (3) decreased PK expression leading to unwantedreductions in cell proliferation, differentiation and/or growth.Over-activity of a PK refers to either amplification of the geneencoding a particular PK or production of a level of PK activity whichcan correlate with a cell proliferation, differentiation and/or growthdisorder (that is, as the level of the PK increases, the severity of oneor more of the symptoms of the cellular disorder increases).Under-activity is, of course, the converse, wherein the severity of oneor more symptoms of a cellular disorder increase as the level of the PKactivity decreases.

As used herein, the terms “prevent”, “preventing” and “prevention” referto a method for barring an organism from acquiring a PK related disorderin the first place.

As used herein, the terms “treat”, “treating” and “treatment” refer to amethod of alleviating or abrogating a PK mediated cellular disorderand/or its attendant symptoms. With regard particularly to cancer, theseterms simply mean that the life expectancy of an individual affectedwith a cancer will be increased or that one or more of the symptoms ofthe disease will be reduced.

The term “organism” refers to any living entity comprised of at leastone cell. A living organism can be as simple as, for example, a singleeukaryotic cell or as complex as a mammal. In a preferred aspect, theorganism is a mammal. In a particularly preferred aspect, the mammal isa human being.

The term “therapeutically effective amount” as used herein refers tothat amount of the compound being administered which will relieve tosome extent one or more of the symptoms of the disorder being treated.In reference to the treatment of cancer, a therapeutically effectiveamount refers to that amount which has the effect of (1) reducing thesize of the tumor, (2) inhibiting (that is, slowing to some extent,preferably stopping) tumor metastasis, (3) inhibiting to some extent(that is, slowing to some extent, preferably stopping) tumor growth,and/or, (4) relieving to some extent (or, preferably, eliminating) oneor more symptoms associated with the cancer.

By “monitoring” is meant observing or detecting the effect of contactinga compound with a cell expressing a particular PK. The observed ordetected effect can be a change in cell phenotype, in the catalyticactivity of a PK or a change in the interaction of a PK with a naturalbinding partner. Techniques for observing or detecting such effects arewell-known in the art. For example, the catalytic activity of a PK maybe observed by determining the rate or amount of phosphorylation of atarget molecule.

Reference to compounds of the invention includes pharmaceuticallyacceptable salts, solvates and hydrates thereof.

“Cell phenotype”refers to the outward appearance of a cell or tissue orthe biological function of the cell or tissue. Examples, withoutlimitation, of a cell phenotype are cell size, cell growth, cellproliferation, cell differentiation, cell survival, apoptosis, andnutrient uptake and use. Such phenotypic characteristics are measurableby techniques well-known in the art.

A “natural binding partner” refers to a polypeptide that binds to aparticular PK in a cell. Natural binding partners can play a role inpropagating a signal in a PK-mediated signal transduction process. Achange in the interaction of the natural binding partner with the PK canmanifest itself as an increased or decreased concentration of thePK/natural binding partner complex and, as a result, in an observablechange in the ability of the PK to mediate signal transduction.

As used herein, “administer” or “administration” refers to the deliveryof a compound or salt of the present invention or of a pharmaceuticalcomposition containing a compound or salt of this invention to anorganism for the purpose of prevention or treatment of a PK-relateddisorder.

A “pharmaceutical composition” refers to a mixture of one or more of thecompounds described herein, or pharmaceutically acceptable salts orprodrugs thereof, with other chemical components, such aspharmaceutically acceptable excipients. The purpose of a pharmaceuticalcomposition is to facilitate administration of a compound to anorganism.

“Pharmaceutically acceptable excipient” refers to an inert substanceadded to a pharmaceutical composition to further facilitateadministration of a compound. Examples, without limitation, ofexcipients include calcium carbonate, calcium phosphate, various sugarsand types of starch, cellulose derivatives, gelatin, vegetable oils andpolyethylene glycols.

“Pharmaceutically acceptable salt” refers to those salts which retainthe biological effectiveness and properties of the parent compound. Suchsalts include:

(1) acid addition salt which is obtained by reaction of the free base ofthe parent compound with inorganic acids such as hydrochloric acid,hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, andperchloric acid and the like, or with organic acids such as acetic acid,oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaricacid, citric acid, succinic acid or malonic acid and the like,preferably hydrochloric acid or (L)-malic acid; and

(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

The inventive compounds described herein may also act as a prodrug. A“prodrug” refers to an agent, which is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent drug is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug.

Indications

The PKs whose catalytic activity is modulated by the compounds of thisinvention include protein tyrosine kinases of which there are two types,receptor tyrosine kinases (RTKS) and cellular tyrosine kinases (CTKs),and serine-threonine kinases (STKs). RTK mediated signal transduction,is initiated by extracellular interaction with a specific growth factor(ligand), followed by receptor dimerization, transient stimulation ofthe intrinsic protein tyrosine kinase activity and phosphorylation.Binding sites are thereby created for intracellular signal transductionmolecules and lead to the formation of complexes with a spectrum ofcytoplasmic signaling molecules that facilitate the appropriate cellularresponse (e.g., cell division, metabolic effects on the extracellularmicroenvironment, etc.). See, Schlessinger and Ullrich, Neuron,9:303–391 (1992).

It has been shown that tyrosine phosphorylation sites on growth factorreceptors function as high-affinity binding sites for SH2 (src homology)domains of signaling molecules. Fantl et al., Cell, 69:413–423 (1992),Songyang et al., Mol. Cell. Biol., 14:2777–2785 (1994), Songyang et al.,Cell, 72:767–778 (1993), and Koch et al., Science, 252:668–678 (1991).Several intracellular substrate proteins that associate with RTKs havebeen identified. They may be divided into two principal groups: (1)substrates that have a catalytic domain, and (2) substrates which lacksuch domain but which serve as adapters and associate with catalyticallyactive molecules. Songyang et al., Cell, 72:767–778 (1993). Thespecificity of the interactions between receptors and SH2 domains oftheir substrates is determined by the amino acid residues immediatelysurrounding the phosphorylated tyrosine residue. Differences in thebinding affinities between SH2 domains and the amino acid sequencessurrounding the phosphotyrosine residues on particular receptors areconsistent with the observed differences in their substratephosphorylation profiles. Songyang et al., Cell, 72:767–778 (1993).These observations suggest that the function of each RTK is determinednot only by its pattern of expression and ligand availability but alsoby the array of downstream signal transduction pathways that areactivated by a particular receptor. Thus, phosphorylation provides animportant regulatory step which determines the selectivity of signalingpathways recruited by specific growth factor receptors, as well asdifferentiation factor receptors.

STKs, being primarily cytosolic, affect the internal biochemistry of thecell, often as a down-line response to a PTK event. STKs have beenimplicated in the signaling process which initiates DNA synthesis andsubsequent mitosis leading to cell proliferation.

Thus, PK signal transduction results in, among other responses, cellproliferation, differentiation, growth and metabolism. Abnormal cellproliferation may result in a wide array of disorders and diseases,including the development of neoplasia such as carcinoma, sarcoma,glioblastoma and hemangioma, disorders such as leukemia, psoriasis,arteriosclerosis, arthritis and diabetic retinopathy and other disordersrelated to uncontrolled angiogenesis and/or vasculogenesis.

A precise understanding of the mechanism by which the compounds of theinvention, in particular, the compounds generated in vivo from thecompounds of the invention, inhibit PKs is not required in order topractice the present invention. However, while not hereby being bound toany particular mechanism or theory, it is believed that the compoundsinteract with the amino acids in the catalytic region of PKs. PKstypically possess a bi-lobate structure wherein ATP appears to bind inthe cleft between the two lobes in a region where the amino acids areconserved among PKs. Inhibitors of PKs are believed to bind bynon-covalent interactions such as hydrogen bonding, van der Waals forcesand ionic interactions in the same general region where the aforesaidATP binds to the PKs. More specifically, it is thought that thecompounds of this invention binds in the general space normally occupiedby the adenine ring of ATP.

In another aspect, the protein kinase, the catalytic activity of whichis modulated by contact with a compound of this invention, is a proteintyrosine kinase, more particularly, a receptor protein tyrosine kinase.Among the receptor protein tyrosine kinases whose catalytic activity canbe modulated with a compound of this invention, or salt thereof, are,without limitation, selected from the group consisting of Met, Flk,FGFR, PDGFR, HER, IR, IGF, IRR, CSFIR, C-Kit, C-fms, flt. In a preferredaspect, the receptor protein tyrosine kinase whose catalytic activitycan be modulated with a compound of this invention, or salt thereof.

The protein tyrosine kinase whose catalytic activity is modulated bycontact with a compound of this invention, or a salt thereof, can alsobe a non-receptor or cellular protein tyrosine kinase (CTK). Thus, thecatalytic activity of CTKs such as, without limitation, Src, Frk, Btk,Csk, Abl, ZAP70, Fes, Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck,Fgr, Aur2 and Yrk may be modulated by contact with a compound or salt ofthis invention.

Still another group of PKs which may have their catalytic activitymodulated by contact with a compound of this invention are theserine-threonine protein kinases such as, without limitation, CDK2, Raf,NEK (including NEK 4a, NEK 4b, NEK 5 and NEK 6) and BUB1.

In another aspect, this invention relates to a method for treating orpreventing a PK related disorder by administering a therapeuticallyeffective amount of a compound of this invention, or a salt thereof, toan organism.

It is also an aspect of this invention that a pharmaceutical compositioncontaining a compound of this invention, or a salt thereof, isadministered to an organism for the purpose of preventing or treating aPK related disorder.

This invention is therefore directed to compounds that modulate PKsignal transduction by affecting the enzymatic activity of RTKs, CTKsand/or STKs, thereby interfering with the signals transduced by suchproteins. More particularly, the present invention is directed tocompounds which modulate RTK, CTK and/or STK mediated signaltransduction pathways as a therapeutic approach to cure many kinds ofsolid tumors, including but not limited to carcinomas, sarcomasincluding Kaposi's sarcoma, erythroblastoma, glioblastoma, meningioma,astrocytoma, melanoma and myoblastoma cancers such as lung cancer, NSCLC(non small cell ling cancer), bone cancer, pancreatic cancer, skincancer, cancer of the head and neck, cutaneous or intraocular melanoma,uterine cancer, ovarian cancer, rectal cancer, cancer of the analregion, stomach cancer, colon cancer, breast cancer, gynecologic tumors(e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma ofthe endometrium, carcinoma of the cervix, carcinoma of the vagina orcarcinoma of the vulva), Hodgkin's Disease, cancer of the esophagus,cancer of the small intestine, cancer of the endocrine system (e.g.,cancer of the thyroid, parathyroid or adrenal glands), sarcomas of softtissues, cancer of the urethra, cancer of the penis, prostate cancer,chronic or acute leukemia, solid tumors of childhood, lynphocyticlymphomas, cancer of the bladder, cancer of the kidney or ureter (e.g.,renal cell carcinoma, carcinoma of the renal pelvis), pediatricmalignancy, neoplasms of the central nervous system (e.g., primary CNSlymphoma, spinal axis tumors, brain stem glioma or pituitary adenomas),cancers of the bloodsuch as acute myeloid leukemia, chronic mueloidleukemia, etc, Barrett's esophagus (pre-malignant syndrome), neoplasticcutaneous disease, psoriasis, mycoses fungoides and benign prostatichypertrophy, diabetes related diseases such as diabetic retinopathy,retinal ischemia and retinal neovascularization, hepatic cirrhosis,cardiovascular disease such as atherosclerosis, immunological diseasesuch as autoimmune disease and renal disease. Preferably, the disease iscancer such as acute myeloid leukemia and colorectal cancer.

Further examples, without limitation, of the types of disorders relatedto inappropriate PK activity that the compounds described herein may beuseful in preventing, treating and studying, are cell proliferativedisorders, fibrotic disorders, metabolic disorders and infectiousdiseases.

Cell proliferative disorders, which may be prevented, treated or furtherstudied by the present invention include cancer, blood vesselproliferative disorders and mesangial cell proliferative disorders.

Blood vessel proliferative disorders refer to disorders related toabnormal vasculogenesis (blood vessel formation) and angiogenesis(spreading of blood vessels). While vasculogenesis and angiogenesis playimportant roles in a variety of normal physiological processes such asembryonic development, corpus luteum formation, wound healing and organregeneration, they also play a pivotal role in cancer development wherethey result in the formation of new capillaries needed to keep a tumoralive. Other examples of blood vessel proliferation disorders includearthritis, where new capillary blood vessels invade the joint anddestroy cartilage, and ocular diseases, like diabetic retinopathy, wherenew capillaries in the retina invade the vitreous, bleed and causeblindness.

Normal vasculogenesis and angiogenesis play important roles in a varietyof physiological processes such as embryonic development, wound healing,organ regeneration and female reproductive processes such as follicledevelopment in the corpus luteum during ovulation and placental growthafter pregnancy. Folkman & Shing, J. Biological Chem.,267(16):10931–10934 (1992). Uncontrolled vasculogenesis and/orangiogenesis has been associated with diseases such as diabetes as wellas with malignant solid tumors that rely on vascularization for growth.Klagsbum & Soker, Current Biology, 3(10):699–702 (1993); Folkham, J.Natl. Cancer Inst., 82:4–6 (1991); Weidner, et al., New Engl. J. Med.,324:1–5 (1991).

As presently understood, the role of VEGF in endothelial cellproliferation and migration during angiogenesis and vasculogenesisindicates an important role for the KDR/FLK-1 receptor in theseprocesses. Diseases such as diabetes mellitus (Folkman, 198, in XIthCongress of Thrombosis and Haemostasis (Verstraeta, et al., eds.), pp.583–596, Leuven University Press, Leuven) and arthritis, as well asmalignant tumor growth may result from uncontrolled angiogenesis. Seee.g., Folkman, N. Engl. J. Med., 285:1182–1186 (1971). The receptors towhich VEGF specifically binds are an important and powerful therapeutictarget for the regulation and modulation of vasculogenesis and/orangiogenesis and a variety of severe diseases which involve abnormalcellular growth caused by such processes. Plowman, et al., DN&P,7(6):334–339 (1994). More particularly, the KDR/FLK-1 receptor's highlyspecific role in neovascularization make it a choice target fortherapeutic approaches to the treatment of cancer and other diseaseswhich involve the uncontrolled formation of blood vessels.

Thus, one aspect of the present invention relates to compounds capableof regulating and/or modulating tyrosine kinase signal transductionincluding KDR/FLK-1 receptor signal transduction in order to inhibit orpromote angiogenesis and/or vasculogenesis, that is, compounds thatinhibit, prevent, or interfere with the signal transduced by KDR/FLK-1when activated by ligands such as VEGF. Although it is believed that thecompounds of the present invention act on a receptor or other componentalong the tyrosine kinase signal transduction pathway, they may also actdirectly on the tumor cells that result from uncontrolled angiogenesis.

Thus, in one aspect, this invention is directed to compounds thatregulate, modulate and/or inhibit vasculogenesis and/or angiogenesis byaffecting the enzymatic activity of the KDR/FLK-1 receptor andinterfering with the signal transduced by KDR/FLK-1. In another aspect,the present invention is directed to compounds which regulate, modulateand/or inhibit the KDR/FLK-1 mediated signal transduction pathway as atherapeutic approach to the treatment of many kinds of solid tumorsincluding, but not limited to, glioblastoma, melanoma and Kaposi'ssarcoma, and ovarian, lung, mammary, prostate, pancreatic, colon andepidermoid carcinoma. In addition, data suggest the administration ofcompounds which inhibit the KDR/Flk-1 mediated signal transductionpathway may also be used in the treatment of hemangioma, restenosis anddiabetic retinopathy.

A further aspect of this invention relates to the inhibition ofvasculogenesis and angiogenesis by other receptor-mediated pathways,including the pathway comprising the flt-I receptor.

Receptor tyrosine kinase mediated signal transduction is initiated byextracellular interaction with a specific growth factor (ligand),followed by receptor dimerization, transient stimulation of theintrinsic protein tyrosine kinase activity and autophosphorylation.Binding sites are thereby created for intracellular signal transductionmolecules which leads to the formation of complexes with a spectrum ofcytoplasmic signaling molecules that facilitate the appropriate cellularresponse, e.g., cell division and metabolic effects to the extracellularmicroenvironment. See, Schlessinger and Ullrich, Neuron, 9:1–20 (1992).

The close homology of the intracellular regions of KDR/FLK-1 with thatof the PDGF-β receptor (50.3% homology) and/or the related flt-Ireceptor indicates the induction of overlapping signal transductionpathways. For example, for the PDGF-β receptor, members of the srcfamily (Twamley et al., Proc. Natl. Acad. Sci. USA, 90:7696–7700(1993)), phosphatidylinositol-3′-kinase (Hu et al., Mol. Cell. Biol.,12:981–990 (1992), phospholipase cγ (Kashishian & Cooper, Mol. Cell.Biol., 4:49–51 (1993)), ras-GTPase-activating protein, (Kashishian etal., EMBO J., 11:1373–1382 (1992), PTP-ID/syp (Kazlauskas et al., Proc.Natl. Acad. Sci. USA, 90:6939–6943 (1993)), Grb2 (Arvidsson et al., Mol.Cell. Biol., 14:6715–6726 (1994)), and the adapter molecules Shc and Nck(Nishimura et al., Mol. Cell. Biol., 13:6889–6896 (1993)), have beenshown to bind to regions involving different autophosphorylation sites.See generally, Claesson-Welsh, Prog. Growth Factor Res., 5:37–54 (1994).Thus, it is likely that signal transduction pathways activated byKDR/FLK-1 include the ras pathway (Rozakis et al., Nature, 360:689–692(1992)), the PI-3′-kinase, the src-mediated and the plcy-mediatedpathways. Each of these pathways may play a critical role in theangiogenic and/or vasculogenic effect of KDR/FLK-1 in endothelial cells.Consequently, a still further aspect of this invention relates to theuse of the organic compounds described herein to modulate angiogenesisand vasculogenesis as such processes are controlled by these pathways.

Conversely, disorders related to the shrinkage, contraction or closingof blood vessels, such as restenosis, are also implicated and may betreated or prevented by the methods of this invention.

Fibrotic disorders refer to the abnormal formation of extracellularmatrices. Examples of fibrotic disorders include hepatic cirrhosis andmesangial cell proliferative disorders. Hepatic cirrhosis ischaracterized by the increase in extracellular matrix constituentsresulting in the formation of a hepatic scar. An increased extracellularmatrix resulting in a hepatic scar can also be caused by a viralinfection such as hepatitis. Lipocytes appear to play a major role inhepatic cirrhosis. Other fibrotic disorders implicated includeatherosclerosis.

Mesangial cell proliferative disorders refer to disorders brought aboutby abnormal proliferation of mesangial cells. Mesangial proliferativedisorders include various human renal diseases such asglomerulonephritis, diabetic nephropathy and malignant nephrosclerosisas well as such disorders as thrombotic microangiopathy syndromes,transplant rejection, and glomerulopathies. The RTK PDGFR has beenimplicated in the maintenance of mesangial cell proliferation. Floege etal., Kidney International, 43:47S–54S (1993).

Many cancers are cell proliferative disorders and, as noted previously,PKs have been associated with cell proliferative disorders. Thus, it isnot surprising that PKs such as, for example, members of the RTK familyhave been associated with the development of cancer. Some of thesereceptors, like EGFR (Tuzi et al., Br. J. Cancer, 63:227–233 (1991),Torp et al., APMIS, 100:713–719 (1992)) HER2/neu (Slamon et al.,Science, 244:707–712 (1989)) and PDGF-R (Kumabe et al., Oncogene,7:627–633 (1992)) are over-expressed in many tumors and/or persistentlyactivated by autocrine loops. In fact, in the most common and severecancers these receptor over-expressions (Akbasak and Suner-Akbasak etal., J. Neurol. Sci., 111:119–133 (1992), Dickson et al., CancerTreatment Res., 61:249–273 (1992), Korc et al., J. Clin. Invest.,90:1352–1360 (1992)) and autocrine loops (Lee and Donoghue, J. Cell.Biol., 118:1057–1070 (1992), Korc et al., supra, Akbasak andSuner-Akbasak et al., supra) have been demonstrated. For example, EGFRhas been associated with squamous cell carcinoma, astrocytoma,glioblastoma, head and neck cancer, lung cancer and bladder cancer. HER2has been associated with breast, ovarian, gastric, lung, pancreas andbladder cancer. PDGFR has been associated with glioblastoma and melanomaas well as lung, ovarian and prostate cancer. The RTK c-met has alsobeen associated with malignant tumor formation. For example, c-met hasbeen associated with, among other cancers, colorectal, thyroid,pancreatic, gastric and hepatocellular carcinomas and lymphomas.Additionally c-met has been linked to leukemia. Over-expression of thec-met gene has also been detected in patients with Hodgkins disease andBurkitts disease.

IGF-R, in addition to being implicated in nutritional support and intype-II diabetes, has also been associated with several types ofcancers. For example, IGF-I has been implicated as an autocrine growthstimulator for several tumor types, e.g. human breast cancer carcinomacells (Arteaga et al., J. Clin. Invest, 84:1418–1423 (1989)) and smalllung tumor cells (Macauley et al., Cancer Res., 50:2511–2517 (1990)). Inaddition, IGF-1, while integrally involved in the normal growth anddifferentiation of the nervous system, also appears to be an autocrinestimulator of human gliomas. Sandberg-Nordqvist et al., Cancer Res.,53:2475–2478 (1993). The importance of IGF-R and its ligands in cellproliferation is further supported by the fact that many cell types inculture (fibroblasts, epithelial cells, smooth muscle cells,T-lymphocytes, myeloid cells, chondrocytes and osteoblasts (the stemcells of the bone marrow)) are stimulated to grow by IGF-1. Goldring andGoldring, Eukaryotic Gene Expression, 1:301–326 (1991). In a series ofrecent publications, Baserga suggests that IGF-R plays a central role inthe mechanism of transformation and, as such, could be a preferredtarget for therapeutic interventions for a broad spectrum of humanmalignancies. Baserga, Cancer Res., 55:249–252 (1995), Baserga, Cell,79:927–930 (1994), Coppola et al., Mol. Cell. Biol., 14:4588–4595(1994).

STKs have been implicated in many types of cancer including, notably,breast cancer (Cance, et al., Int. J. Cancer, 54:571–77 (1993)).

The association between abnormal PK activity and disease is notrestricted to cancer. For example, RTKs have been associated withdiseases such as psoriasis, diabetes mellitus, endometriosis,angiogenesis, atheromatous plaque development, Alzheimer's disease, vonHippel-Lindau disease, epidermal hyperproliferation, neurodegenerativediseases, age-related macular degeneration and hemangiomas. For example,EGFR has been indicated in corneal and dermal wound healing. Defects inInsulin-R and IGF-1R are indicated in type-II diabetes mellitus. A morecomplete correlation between specific RTKs and their therapeuticindications is set forth in Plowman et al., DN&P, 7:334–339 (1994).

As noted previously, not only RTKs but CTKs including, but not limitedto, src, abl, fps, yes, fyn, lyn, Ick, bik, hck, fgr, AUR¹, AUR² and yrk(reviewed by Bolen et at, FASEB J., 6:3403–3409 (1992)) are involved inthe proliferative and metabolic signal transduction pathway and thuscould be expected, and have been shown, to be involved in manyPTK-mediated disorders to which the present invention is directed. Forexample, mutated src (v-src) has been shown to be an oncoprotein (pp60^(v-src)) in chicken. Moreover, its cellular homolog, the proto-oncogenepp60^(c)-sc transmits oncogenic signals of many receptors.Over-expression of EGFR or HER2/neu in tumors leads to the constitutiveactivation of pp60^(c sc) which is characteristic of malignant cells butabsent in normal cells. On the other hand, mice deficient in theexpression of c-src exhibit an osteopetrotic phenotype, indicating a keyparticipation of c-src in osteoclast function and a possible involvementin related disorders.

Similarly, Zap70 has been implicated in T-cell signaling which mayrelate to autoimmune disorders.

STKs have been associated with inflammation, autoimmune disease,immunoresponses, and hyperproliferation disorders such as restenosis,fibrosis, psoriasis, osteoarthritis and rheumatoid arthritis.

PKs have also been implicated in embryo implantation. Thus, thecompounds of this invention may provide an effective method ofpreventing such embryo implantation and thereby be useful as birthcontrol agents.

In yet another aspect, the compounds of the instant invention can alsobe used as anti-infective agents.

Finally, both RTKs and CTKs are currently suspected as being involved inhyperimmune disorders.

Pharmaceutical Compositions and Use

A compound of the present invention or a physiologically acceptable saltthereof, can be administered as such to a human patient or can beadministered in pharmaceutical compositions in which the foregoingmaterials are mixed with suitable carriers or excipient(s). Techniquesfor formulation and administration of drugs may be found in “Remington'sPharmacological Sciences,” Mack Publishing Co., Easton, Pa., latestedition.

Routes of Administration

Suitable routes of administration may include, without limitation, oral,intraoral, rectal, transmucosal or intestinal administration orintramuscular, epicutaneous, parenteral, subcutaneous, transdermal,intramedullary, intrathecal, direct intraventricular, intravenous,intravitreal, intraperitoneal, intranasal, intramuscular, intradural,intrarespiratory, nasal inhalation or intraocular injections. Thepreferred routes of administration are oral and parenteral.

Alternatively, one may administer the compound in a local rather thansystemic manner, for example, via injection of the compound directlyinto a solid tumor, often in a depot or sustained release formulation.

Furthermore, one may administer the drug in a targeted drug deliverysystem, for example, in a liposome coated with tumor-specific antibody.The liposomes will be targeted to and taken up selectively by the tumor.

Composition/Formulation

Pharmaceutical compositions of the present invention may be manufacturedby processes well known in the art, e.g., by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping, lyophilizing processes or spray drying.

Pharmaceutical compositions for use in the methods of the presentinvention may be prepared by any methods of pharmacy, but all methodsinclude the step of bringing in association the active ingredient withthe carrier which constitutes one or more necessary ingredients. Inparticular, pharmaceutical compositions for use in accordance with thepresent invention may be formulated in conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, patches, syrups, elixirs, gels, powders, magmas,lozenges, ointments, creams, pastes, plasters, lotions, discs,suppositories, nasal or oral sprays, aerosols and the like.

For injection, the compounds of the invention may be formulated inaqueous solutions, preferably in physiologically compatible buffers suchbuffers with or without a low concentration of surfactant or cosolvent,or physiological saline buffer. For transmucosal administration,penetrants appropriate to the barrier to be permeated are used in theformulation. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated by combiningthe active compounds with pharmaceutically acceptable carriers wellknown in the art. Such carriers enable the compounds of the invention tobe formulated as tablets, pills, lozenges, dragees, capsules, liquids,gels, syrups, slurries, suspensions and the like, for oral ingestion bya patient. Pharmaceutical preparations for oral use can be made using asolid excipient, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding other suitableauxiliaries if desired, to obtain tablets or dragee cores. Usefulexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol, cellulose preparations such as,for example, maize starch, wheat starch, rice starch and potato starchand other materials such as gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinyl-pyrrolidone (PVP). If desired, disintegrating agents may beadded, such as cross-linked polyvinyl pyrrolidone, agar, or alginicacid. A salt such as sodium alginate may also be used.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical compositions which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with a fillersuch as lactose, a binder such as starch, and/or a lubricant such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, liquid polyethyleneglycols, cremophor, capmul, medium or long chain mono- di- ortriglycerides. Stabilizers may be added in these formulations, also.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray using a pressurized pack or a nebulizer and a suitable propellant,e.g., without limitation, dichlorodifluoromethane,trichlorofluoromethane, dichlorotetra-fluoroethane or carbon dioxide. Inthe case of a pressurized aerosol, the dosage unit may be controlled byproviding a valve to deliver a metered amount. Capsules and cartridgesof, for example, gelatin for use in an inhaler or insulator may beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The compounds may also be formulated for parenteral administration,e.g., by bolus injection or continuous infusion. Formulations forinjection may be presented in unit dosage form, e.g., in ampoules or inmulti-dose containers, with an added preservative. The compositions maytake such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulating materials such assuspending, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration includeaqueous solutions of a water soluble form, such as, without limitation,a salt, of the active compound. Additionally, suspensions of the activecompounds may be prepared in a lipophilic vehicle. Suitable lipophilicvehicles include fatty oils such as sesame oil, synthetic fatty acidesters such as ethyl oleate and triglycerides, or materials such asliposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers and/or agents that increase the solubilityof the compounds to allow for the preparation of highly concentratedsolutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile, pyrogen-free water,before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, using, e.g., conventional suppositorybases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as depot preparations. Such long acting formulationsmay be administered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. A compound of thisinvention may be formulated for this route of administration withsuitable polymeric or hydrophobic materials (for instance, in anemulsion with a pharmacologically acceptable oil), with ion exchangeresins, or as a sparingly soluble derivative such as, withoutlimitation, a sparingly soluble salt.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Inaddition, certain organic solvents such as dimethylsulfoxide also may beemployed, although often at the cost of greater toxicity.

Additionally, the compounds may be delivered using a sustained-releasesystem, such as semipermeable matrices of solid hydrophobic polymerscontaining the therapeutic agent. Various sustained-release materialshave been established and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

The pharmaceutical compositions herein also may comprise suitable solidor gel phase carriers or excipients. Examples of such carriers orexcipients include, but are not limited to, calcium carbonate, calciumphosphate, various sugars, starches, cellulose derivatives, gelatin, andpolymers such as polyethylene glycols.

Many of the PK modulating compounds of the invention may be provided asphysiologically acceptable salts wherein the claimed compound may formthe negatively or the positively charged species. Examples of salts inwhich the compound forms the positively charged moiety include, withoutlimitation, quaternary ammonium (defined elsewhere herein), salts suchas the hydrochloride, sulfate, malate, carbonate, lactate, tartrate,maleate, succinate wherein the nitrogen atom of the quaternary ammoniumgroup is a nitrogen of the selected compound of this invention which hasreacted with the appropriate acid. Salts in which a compound of thisinvention forms the negatively charged species include, withoutlimitation, the sodium, potassium, calcium and magnesium salts formed bythe reaction of a carboxylic acid group in the compound with anappropriate base (e.g. sodium hydroxide (NaOH), potassium hydroxide(KOH), Calcium hydroxide (Ca(OH)₂), etc.).

Dosage

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in anamount sufficient to achieve the intended purpose, i.e., the modulationof PK activity or the treatment or prevention of a PK-related disorder.

More specifically, a therapeutically effective amount means an amount ofcompound effective to prevent, alleviate or ameliorate symptoms ofdisease or prolong the survival of the subject being treated.

Determination of a therapeutically effective amount is well within thecapability of those skilled in the art, especially in light of thedetailed disclosure provided herein.

For any compound used in the methods of the invention, thetherapeutically effective amount or dose can be estimated initially fromcell culture assays. Then, the dosage can be formulated for use inanimal models so as to achieve a circulating concentration range thatincludes the IC₅₀ as determined in cell culture (i.e., the concentrationof the test compound which achieves a half-maximal inhibition of the PKactivity). Such information can then be used to more accuratelydetermine useful doses in humans.

Toxicity and therapeutic efficacy of the compounds described herein canbe determined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., by determining the IC₅₀ and the LD₅₀ (bothof which are discussed elsewhere herein) for a subject compound. Thedata obtained from these cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage mayvary depending upon the dosage form employed and the route ofadministration utilized. The exact formulation, route of administrationand dosage can be chosen by the individual physician in view of thepatient's condition. (See e.g., Fingl, et al., 1975, in “ThePharmacological Basis of Therapeutics”, Ch. 1 p. 1).

Dosage amount and interval may be adjusted individually to provideplasma levels of the active species which are sufficient to maintain thekinase modulating effects. These plasma levels are referred to asminimal effective concentrations (MECs). The MEC will vary for eachcompound but can be estimated from in vitro data, e.g., theconcentration necessary to achieve 50–90% inhibition of a kinase may beascertained using the assays described herein. Dosages necessary toachieve the MEC will depend on individual characteristics and route ofadministration. HPLC assays or bioassays can be used to determine plasmaconcentrations.

Dosage intervals can also be determined using MEC value. Compoundsshould be administered using a regimen that maintains plasma levelsabove the MEC for 10–90% of the time, preferably between 30–90% and mostpreferably between 50–90%. At present, the therapeutically effectiveamounts of the inventive compounds described herein may range fromapproximately 25 mg/m² to 1000-mg/m² perday. Even more preferably 25mg/m² to 150 mg/m².

In cases of local administration or selective uptake, the effectivelocal concentration of the drug may not be related to plasmaconcentration and other procedures known in the art may be employed todetermine the correct dosage amount and interval.

The amount of a composition administered will, of course, be dependenton the subject being treated, the severity of the affliction, the mannerof administration, the judgment of the prescribing physician, etc.

Packaging

The compositions may, if desired, be presented in a pack or dispenserdevice, such as an FDA approved kit, which may contain one or more unitdosage forms containing the active ingredient. The pack may for examplecomprise metal or plastic foil, such as a blister pack. The pack ordispenser device may be accompanied by instructions for administration.The pack or dispenser may also be accompanied by a notice associatedwith the container in a form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals, which noticeis reflective of approval by the agency of the form of the compositionsor of human or veterinary administration. Such notice, for example, maybe of the labeling approved by the U.S. Food and Drug Administration forprescription drugs or of an approved product insert. Compositionscomprising a compound of the invention formulated in a compatiblepharmaceutical carrier may also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition. Suitableconditions indicated on the label may include treatment of a tumor,inhibition of angiogenesis, treatment of fibrosis, diabetes, and thelike.

EXAMPLES

The following examples are given to illustrate the present invention. Itshould be understood, however, that the invention is not to be limitedto the specific conditions or details described in these examples.

The numbering in the examples corresponds to the numbering in the Tablesherein. Reaction schemes and example numbers beginning with a letter (I)relate to pyridine compounds, whereas those beginning with a letter (II)relate to pyrazine compounds. Example numbers beginning with L arelibrary syntheses. Example numbers having a letter notation (a, b, c,etc.) illustrate the synthesis of reagents subsequently used in thesynthesis of the inventive compounds, which have a number notation (1,2, 3, etc.). Reagents can be synthesized as shown herein, or areavailable from commercial sources (e.g., Aldrich, Milwaukee, Wis.;Acros, Morris Plains, N.J.; Biosynth International, Naperville, Ill.;Frontier Scientific, Logan, Utah; TCI America, Portland, Oreg.;Combi-Blocks, San Diego, Calif.; Matrix Scientific, Columbia, S.C.;Acros, Morris Plains, N.J.; Alfa Aesar, Ward Hill, Mass.; ApolloScientific, UK; etc.) or can be synthesized by procedures known in theart. When a general or exemplary synthetic procedure is referred to, oneskilled in the art can readily determine the appropriate reagents, ifnot indicated, extrapolating from the general or exemplary procedures.

In the general procedures 1–43 described herein, although some of theprocedures are generalized and exemplary, past tense is used to indicatethat these general procedures were the procedures used to synthesize thecompounds. Some of the general procedures are given as examples forpreparing specific compounds. One skilled in the art can readily adaptsuch procedures to the synthesis of other compounds. It should beunderstood that R groups shown in the general procedures are meant to begeneric and non-limiting, and do not correspond to definitions of Rgroups elsewhere in this document. Each such R group represents one ormultiple chemical moieties that can be the same or different from otherchemical moieties also represented by the same R symbol. Moreover,representation of an unsubstituted position in structures shown orreferred to in the general procedures is for convenience and does notpreclude substitution as described elsewhere herein. For specific groupsthat can be present, either as R groups in the general procedures or asoptional substituents not shown, refer to the descriptions in theremainder of this document, including the claims, summary and detaileddescription. It should be further understood that compound numbers shownin the general schemes and general procedures in the Examples are forconvenient reference only, and do not correspond to the numbers usedelsewhere throughout this document. For example, the nitropyridinecompound (1) in general scheme I is different from the compound offormula 1

described herein.

General Scheme I for the Synthesis of5-Aryl-3-(Substituted-Benzyloxy)-Pyridin-2-ylamine (6):

General Scheme II for the Synthesis of5-Aryl-3-(Substituted-Benzyloxy)-Pyrazin-2-ylamine

General Procedure 1 for the Synthesis of5-Bromo-3-(Substituted-Benzyloxy)-Pyridin-2-ylamine (5):

1. Preparation of 3-(substituted-benzyloxy)-2-nitro-pyridine (3): To astirred solution of Cs₂CO₃ (1.0 molar equivalent)) in DMF (0.2 M) undera N₂ atmosphere containing 3-hydroxy-4-nitro-pyridine (Aldrich, 1.0molar equivalent) was added substituted benzyl bromide (1.0 molarequivalent). The mixture was stirred for 6 h at ambient temperature. Thereaction was then diluted with EtOAc, and partitioned with H₂O. Theaqueous layer was extracted with EtOAc twice. The organic layers werethen combined, washed with H₂O and brine, dried over Na₂SO₄, filtered,and concentrated to dryness under vacuum to yield3-(substituted-benzyloxy)-2-nitro-pyridine (3) as a solid.

2. Preparation of 3-(substituted-benzyloxy)-pyridin-2-ylamine (4): To astirred mixture of AcOH and EtOH (1.3:1) was suspended3-(substituted-benzyloxy-2-nitro-pyridine (1.0 molar equivalent, 1 M)and iron chips (1.0 molar equivalent). The reaction was heated slowly toreflux and allowed to stir for 1 hr. The reaction was cooled to roomtemperature then filtered through a pad of celite. The resultingfiltrate was neutralized with conc. NH₄OH, and then extracted with EtOAcfor three times. The combined organic extracts were washed withsaturated NaHCO₃, H₂O, and brine, dried over Na₂SO₄, filtered andconcentrated to dryness under vacuum to yield3-(substituted-benzyloxy)-pyridin-2-ylamine (4) as a solid.

3. Preparation of 5-bromo-3-(substituted benzyloxy)-pyridin-2-ylamine(5): A stirring solution of 3-(substituted-benzyloxy)-pyridin-2-ylamine(4) (1.0 molar equivalent) in acetonitrile was cooled to 0° C. using anice bath. To this solution was added N-bromosuccinimide (Aldrich, 1.0molar equivalent) portionwise. The reaction was stirred at 0° C. for 15min. The reaction was concentrated to dryness under vacuum. Theresulting dark oil was dissolved in EtOAc and partitioned with H₂O. Theorganic was then washed with saturated NaHCO₃ twice and brine once.Activated charcoal was added to the organic layer and warmed to reflux.The solution was then cooled to room temperature and filtered through apad of celite. The organic was then concentrated to dryness under vacuumto one third the original volume. The solids were then filtered off toyield 5-bromo-3-(substituted benzyloxy)-pyridin-2-ylamine (5) as asolid.

General Procedure 2 for the Synthesis of5-Bromo-3-(Substituted-Benzyloxy)-Pyrazin-2-ylamine.

To an ice cooled solution of substituted benzyl alcohol (1.0 molarequivalent) and anhydrous tetrahydrofuran (0.14 M) was added sodiumhydride (1.0 molar equivalent) slowly under nitrogen atmosphere. Afterstirring for 30 minutes, 3,5-dibromopyrazin-2-ylamine (1.0 molarequivalent) in tetrahydrofuran (0.56 M) was added via an addition funnelat a fast dropwise rate. Once the addition was complete the ice bath wasremoved and the reaction was refluxed under nitrogen and monitored byreversed phase HPLC. After 18 hr HPLC showed that the majority of thestarting 3,5-dibromopyrazin-2-ylamine had been consumed and the reactionwas allowed to cool to room temperature. The reaction mixture wasconcentrated, diluted with ethyl acetate, and washed with brine. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated in vacuum. The crude product was purified using a silicagel eluting with 1:1 ethyl acetate/dichloromethane to yield the5-bromo-3-(substituted-benzyloxy)-pyrazin-2-ylamine as a white solid in60–90% yield.

General Procedure 3 for the Synthesis of5-Aryl-3-(Substituted-Benzyloxy)-Pyridin-2-ylamine and5-Aryl-3-(Substituted-Benzyloxy)-Pyrazin-2-ylamine.

A mixture of 5-bromo-3-(substituted-benzyloxy)-pyridin-2-ylamine or5-bromo-3-(substituted-benzyloxy)-pyrazin-2-ylamine (1 molarequivalent), aryl boronic acid or ester (1.2 molar equivalent),bis(triphenylphosphine) palladium 11 chloride (0.03 molar equivalent)and sodium carbonate (3.0 molar equivalent) in ethylene glycol dimethylether and water (10:0.5, 0.03 M) was de-gassed and charged with nitrogenfor three times, and then heated to reflux under nitrogen for overnight.The reaction was cooled to ambient temperature and diluted with ethylacetate. The mixture was washed with water, brine, dried over Na₂SO₄,and purified on a silica gel column to afford5-aryl-3-(substituted-benzyloxy)-pyridin-2-ylamine, or5-aryl-3-(substituted-benzyloxy)-pyrazin-2-ylamine.

General Procedure 4 for Amidation Reaction of6-amino-5-(substituted-benzyloxy)-pyridin-3-yl]-benzoic acid:

To a solution of 6-amino-5-(substituted-benzyloxy)-pyridin-3-yl]-benzoicacid (1 molar equivalent), 1-hydroxybenzotriazole hydrate (HOBT, 1.2molar equivalent), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC, 1.2 molar equivalent) in DMF (0.2 M) was added amine(1.2 molar equivalent). The reaction solution was stirred at roomtemperature for overnight, then diluted with EtOAc, and partitioned withH₂O. The organic was separated and the aqueous was extracted with EtOAc.The organic layers were combined, washed with saturated NaHCO₃, andconcentrated to dryness under vacuum. The material was purified usingcolumn chromatography (silica gel, 99:1 to 95:5 CH₂Cl₂/MeOH). Thefractions containing product were concentrated under vacuum to yield theamide product.

General procedure 5 for the preparation of3-(substituted-benzyloxy)-5-(3-dialkylaminomethyl-1H-indol-5-yl)-pyridin-2-ylamine:

To a solution of benzotriazole (1.0 molar equivalent) in dichloromethane(0.2 M) was added amine (1.0 molar equivalent). The reaction was stirredfor 5 minutes at room temperature after which formaldehyde (37% by wt,1.0 molar equivalent) was added and the reaction was capped and stirredat room temperature for 3 hr. Once TLC (10% ethyl acetate:dichloromethane) showed the consumption of starting benzotriaziole thereaction was dried with anhydrous magnesium sulfate (10 g), filtered andconcentrated in vacuo. The crude product was purified with a silica gelcolumn eluting with 1:1 ethyl acetate: dichloromethane to yield thedesired product as a white solid.

To a solution of the aminomethylbenzotriazole intermediate (1.0 molarequivalent) in dichloromethane (0.43 M) was added aluminum chloride (2.0molar equivalent), and then followed by3-(2,6-Dichloro-benzyloxy)-5-(1H-indol-5-yl)-pyridine-2-ylamin (1.1molar equivalent). The reaction was capped and heated with stirring to40° C. for 3–4 hr. The reaction was then removed from the heat andallowed to cool to room temperature. The reaction mixture was dilutedwith sodium hydroxide (0.2 M) and chloroform, recapped and vigorouslystirred at room temperature to dissolve the residue in the vial. Thechloroform was extracted away from the aqueous, dried over anhydroussodium sulfate and concentrated in vacuo. The crude product was purifiedwith a silica gel column, first eluting with 1:1, ethyl acetate:dichloromethane, to elute the less polar impurities and then eluting theproduct with 90:9:1, chloroform:methanol:ammonium hydroxide. (Yields10–67%.)

General Procedure 6 for the synthesis of3-(Substituted-benzyloxy)-5-phenyl-pyridin-2-ylamine using example 1–88:

To a solution of 3-benzyloxy-5-phenyl-pyridin-2-ylamine (Example I-87,3.27 g, 11.8 mmol) in methanol (30 mL) was added Pd(OH)₂ (2.5 g, 2.37mmol). The mixture was degassed and charged with hydrogen three times,and then stirred under hydrogen balloon for 5 hr. The reaction wasfiltered through a celite pad, washed with methanol, and condensed.After high vacuum dry, 2-amino-5-phenyl-pyridin-3-ol was obtained (2.04g, 93% yield). MS m/z 187 [M+1].

To a solution of 2-amino-5-phenyl-pyridin-3-ol (2.04 g, 10.95 mmol) inTHF (anhydrous, 30 mL) was added NaH (1.31 g, 32.85 mmol) slowly. Themixture was stirred under nitrogen for 20 minutes, and then tritylchloride (3.66 g, 13.14 mmol) was added. The reaction was stirred atroom temperature for over night under nitrogen. The solvent wasevaporated, and the residue was dissolved in dichloromethane, washedwith water, and dried over Na₂SO₄. After filtration and condensation,the crude product was purified on a silica gel column eluting withEtOAc-Hexane (1:10) to provide 5-phenyl-2-(trityl-amino)-pyridin-3-ol(1.09 g, 23% yield). MS m/z 427 [M+1].

To a solution of 5-phenyl-2-(trityl-amino)-pyridin-3-ol (100 mg, 0.24mmol) in THF (3 mL) was added Cs₂CO₃ (79 mg, 0.24 mmol). The mixture wasstirred at room temperature for 20 minutes, and then3-methoxybenzylbromide (0.037 mL, 0.26 mmol) was added. The reaction wasstirred at room temperature overnight, diluted with dichloromethane (5mL), and filtered to remove the salts. The solvents were evaporated, andthe residue was dissolved in 10% trifluoroacetic acid in dichloromethane(2 mL). The reaction was stirred for 2 hr, and evaporated. The residuewas dissolved in dichloromethane, washed by sat. NaHCO₃, and dried overNa₂SO₄. After filtration and concentration, the crude product waspurified on a silica gel column eluting with methanol-dichloromethane(from 3% to 15% gradient) to provide3-(3-methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine as a white solid(43.5 mg, 60% yield).

General Procedure 7 for the Synthesis of3-(Substituted-benzyloxy)-5-Aryl-pyridin-2-ylamine using Example I-106:

To a solution of2-amino-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-3-ol (preparedaccording to the procedures for 2-amino-5-phenyl-pyridin-3-ol in ExampleI-88) (45.5 mg, 0.14 mmol) in DMF (3 mL) at 0° C. was added NaH (60% inoil) (5.6 mg, 0.14 mmol) and the mixture was stirred at 0° C. for 20min. Then 1-Bromomethyl-3-nitro-benzene was added and the mixture wasstirred at 0° C. for 1 hr and at room temperature for 2 hr. Cold 1 Naqueous HCl (0.1 mL) was added and the solvent was removed under reducedpressure. The residue was purified with silica gel chromatography(CH₂Cl₂:MeOH:NH₄OH=100:3:0.3) to give5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-(3-nitro-benzyloxy)-pyridin-2-ylamineas yellow solid (44 mg, 68%).

General Procedure 8 for the Synthesis of{4-[6-Amino-5-(substituted-benzyloxy)-pyridin-3-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanoneusing Example I-111:

1. 6-Amino-5-benzyloxy-nicotinic acid was prepared according toprocedure 3 from 3-benzyloxy-5-bromo-pyridin-2-ylamine and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid. MS m/z321 (M+1).

2.[4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenyl]-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanonewas prepared following procedure 4 using 6-amino-5-benzyloxy-nicotinicacid and (2R)-pyrrolidin-1-ylmethyl-pyrrolidine (prepared in ExampleI-39). MS m/z 457 (M+1).

3. To a solution of[4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenyl]-[(2R)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone(2.28 g, 5.00 mmol) in methanol (25 mL) was added 10% Pd/C (100 mg). Themixture was degassed and charged with hydrogen for three times, and thenstirred under hydrogen balloon overnight. The reaction was filteredthrough a celite pad, washed with methanol, and condensed. After highvacuum dry,[4-(6-amino-5-hydroxy-pyridin-3-yl)-phenyl]-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanonewas obtained (1.74 g, 95% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 7.79 (s,1H), 7.54 (m, 3H), 7.46 (m, 2H), 7.14 (s, 1H), 5.68 (s, 2H), 4.22 (m,1H), 3.45 (m, 2H), 2.66 (m, 1H), 2.52 (m, 4H), 1.96 (m, 2H), 1.84 (m,3H), 1.64 (m, 4H); MS m/z 367 (M+1).

4. To a stirred solution of[4-(6-amino-5-hydroxy-pyridin-3-yl)-phenyl]-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone(100 mg, 0.27 mmol) in anhydrous DMF(15 mL) under a N₂ atmospherecontaining, at 0° C., sodium hydride (60% dispersion in mineral oil, 11mg, 0.49 mmol) was added. The mixture was allowed to stir at 0° C. for30 min. 1-(Bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene (0.046 mL,0.27 mmol) was added. The mixture was stirred at room temperature for 2hr. The reaction was diluted with EtOAc, and partitioned with H₂O. Theaqueous layer was extracted with EtOAc (2×25 mL). The organic layerswere combined, washed with H₂O (1×15 mL), brine (1×15 mL), dried overMgSO₄, filtered, concentrated, and purified on a silica gel column toyield{4-[6-amino-5-(4-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanoneas off-white crystals.

General Procedure 9 for the Synthesis 2-Dialkylamino-ethanesulfonic acid[6-amino-5-(substituted-benzyloxy)-pyridin-3-yl]-phenyl-amide usingExample I-243.

1. To a solution of4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (5 g, 22.8mmol) in dichloromethane (120 mL) was added N-methyl morpholine (7.5 mL,68.4 mmol). This mixture was cooled to 0° C. under nitrogen atmosphere.2-Chloroethanesulfonyl chloride (2.5 mL, 23.9 mmol) in dichloromethane(60 mL) was then added drop wise with stirring. Once the addition wascomplete the flask was stirred at 0° C. for 1 hr and then at roomtemperature while monitoring by TLC (1:1 ethyl acetate:hexanes) andstaining with ninhydrin. After 4 h stirring some starting boronic esterstill remained and an additional 0.2 equivalents (0.5 mL) of2-chloroethanesulfonyl chloride in dichloromethane (25 mL) was addeddrop wise at room temperature. After 1 hr the boronic ester had beenconsumed as shown by TLC and the total reaction volume was reduced byone-half via rotary evaporation. The contents were diluted with ethylacetate (200 mL), washed with 50% brine (2×100 mL), dried over anhydroussodium sulfate and concentrated in vacuum. The crude product waspurified using silica gel (120 g) and eluting with 10% ethyl acetate,dichloromethane to yield ethenesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amidea as awhite solid (6.2 g, 20.2 mmol, 89% yield). ¹H NMR (CDCl₃, 300 MHz), δ7.76 (d, J=8.4, 2H), 7.12 (d, J=8.45, 2H) 6.65 (s, 1H), 6.55 (dd,J=9.77, 6.7, 1H), 6.31 (d, J=16.54, 1H), 5.96 (d, J=9.8, 1H), 1.33 (s,12H).

2. To a solution of ethenesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (0.500g, 1.6 mmol) in methanol (5 mL) was added diethylamine (0.707 g, 4.0mmol) in methanol (5 mL), and the reaction was stirred at roomtemperature and monitored by TLC (1:1 Ethyl acetate:hexanes). After 2 hrthe reaction was concentrated in vacuum and the residue partitionedbetween ethyl acetate (50 mL) and water (50 mL). The ethyl acetate wasthen washed with 50% brine (1×50 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuum. Crude product was purifiedusing a 10 g prepacked silica gel column, eluting with 1:1 ethylacetate: dichloromethane to provide 2-diethylamino-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide as awhite solid (0.346 g, 0.90 mmol, 56%). ¹H NMR (CDCl₃, 300 MHz) δ 7.78(d, J=6.65, 2H) 7.15 (d, J=6.66, 2H), 3.20 (m, 2H), 3.0 (m, 2H), 2.55(q, J=7.15, 7.16 4H), 1.34 (s, 12H), 1.05 (t, J=7.19, 6H).

3. 2-diethylamino-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl)amidewas prepared following the general Suzuki coupling procedure 3 from5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and2-diethylamino-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide preparedin part 2 as a white solid in 60% yield.

General Procedure 10:

1: 4-(4,4,5,5-tetramethyl 1,3,2 dioxaborolan-2-yl) aniline (3 g, 0.013mol) was dissolved in dichloromethane (350 mL) to which pyridine (1.02g, 0.013 mol) and 4-nitrophenyl chloroformate was added. The reactionwas stirred for 13 hr where TLC analysis showed consumption of allstarting materials. The solution was washed with saturated NaHCO₃ (3×50mL), water (3×50 mL) and brine (3×50 mL). The organic layer was driedover Na₂SO₄ and solvent removed to yield a white crystalline solid[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acidphenyl ester, 4.45 g, 91%. ¹H NMR (CDCl₃ 300 MHz) δ 1.4 (s, 12H), 7.1(brs, 1H), 7.3 (d, 2H), 7.5 (d, 2H), 7.8 (d, 2H), 8.3 (d, 2H).

2: [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamicacid phenyl ester (500 mg, 1.3 mmol) was dissolved in anhydrousdichloromethane (0.5 mL) and triethylamine (0.187 mL, 1.3 mmol). To thisstirred solution was added 1-methyl piperazine (or any other amine)(0.144 mL, 1.3 mmol). The solution turned yellow instantly, and ticanalysis showed consumption of all starting material. The reaction waswashed with water (3×500 mL), saturated sodium bicarbonate (2×200 mL)and dried prior to removal of solvents in vacuo. The boronic esters wereused without purification.

3: To a mixture of 2.1 mL of DME and 2.8 mL of 2N Na₂CO₃ was added 100mg of the bromide scaffold, 1 equivalent of the boronic acid, and 5 mol% of Pd(PPh₃)₄. The reaction was stirred and heated at 80° C. overnightin a two dram vial. The crude mixture was filtered through ceolite andextracted with EtOAc (2×100 mL). The combined extracts were washed withNaHCO₃ (1×100 mL), followed by water (1×100 mL), and then saturatedbrine (1×100 mL). The resulting mixture was concentrated in vacuum. Theresidue was dissolved in hexane and purified via column chromatography.

General Procedure 11:

1: To a solution of3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine (10.0 g,33.2 mmol) in acetonitrile (600 mL) and acetic acid (120 mL) was addedN-iodosuccinimide (11.2 g, 49.8 mmol). The mixture was stirred at roomtemperature for 4 hr and the reaction was quenched with Na₂S₂O₅solution. After evaporation, the residue was partitioned between ethylacetate and water. The organic layer was washed with 2N NaOH solution,brine, and dried over Na₂SO₄. The crude product was purified on a silicagel column to provide3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine(7.1 g, 50% yield). MS m/z 427 [M+1]

2: To a solution of3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine(7.1 g, 16.6 mmol) and prop-2-ynyl-carbamic acid tert-butyl ester (3.1g, 20.0 mmol) in THF (60 mL) and Et₃N (60 mL) was added Cul (63 mg, 0.3mmol) and Pd(PPh₃)₄ (384 mg, 0.3 mmol). The mixture was stirred undernitrogen and monitored by TLC until the reaction was complete. Themixture was extracted with EtOAc and washed by water. The crude productwas purified on a silica gel column eluting with 20–40% EtOAc in hexanesto provide(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-prop-2-ynyl)-carbamicacid tert-butyl ester (2.2 g, 29% yield).

3: The solution of(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-carbamicacid tert-butyl ester in 25% TFA in dichloromethane was stirred for 2hr, then washed by 2N NaOH, water twice, brine, dried over Na₂SO₄. Afterfiltration and evaporation,5-(3-amino-prop-1-ynyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylaminewas obtained in 93% yield.

4: To a solution of5-(3-amino-prop-1-ynyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine(0.282 mmol, 1 eq) and 4-nitrophenyl chloroformate (1 eq) in anhydrousdichloromethane (10 mL) was added pyridine (1 eq). The reaction wasstirred for 4 hr under nitrogen, and then the selected amine (1 eq) andtriethylamine (1 eq) were added. The mixture was refluxed for 5 minutesand cooled to room temperature. The reaction mixture was washed withwater. The organic layer was evaporated and purified on a silica gelcolumn eluting with 0–20% methanol in dichloromethane on prepackedsilica columns. Final yields varied between 24% and 71%.

General Procedure 12:

1: To a solution of5-(3-amino-prop-1-ynyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine(prepared in procedure 11) (400 mg, 1.1 mmol) in dichloromethane (17 mL)was added chloroacetyl chloride (153 mg, 1.4 mmol). The reaction wasstirred at room temperature with TLC monitor of the completion of thereaction. After the completion, the solvent was evaporated to get thecrude product.

2: To a solution ofN-(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-prop-2-ynyl)-2-chloro-acetamide(1 eq) in acetonitrile (5 eq) was added the individual amine (5 eq). Themixture was refluxing under nitrogen overnight. After evaporation ofsolvent, the residue was purified on a silica gel column eluting with1–10% methanol in dichloromethane to provide the product with yieldsvaried between 47% to 97%.

General Procedure 13:

1. To a stirred solution of 2-amino-3-benzyloxypyridine (42.0 g, 0.21mol) in CH₃CN (600 mL) at 0° C. was added N-bromosuccinimide (37.1 g,0.21 mol) over 30 minutes. The mixture was stirred for 0.5 hr, afterwhich the reaction was then diluted with EtOAc (900 mL) and partitionedwith H₂O (900 mL). The organic layer was washed with brine and dried(Na₂SO₄), filtered and concentrated to dryness under vacuum to yield3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mol, 53%). ¹H NMR(CDCl₃, 300 MHz) δ 4.63–4.78 (brs, 2H), 5.04 (s, 2H), 7.07 (d, 1H, J,1.8 Hz), 7.33–7.42 (m, 5H), 7.73 (d, 1H, J, 1.8 Hz).

2. To a stirred mixture of 3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0g, 0.11 mol) in a mixture of DME (600 mL) and H₂O (600 mL) was added4-carboxymethylboronic acid (29.9 g, 0.11 mol), Pd(PPh₃)₄ (6.4 g, 5.55mmol), and Na₂CO₃ (82.0 g, 0.78 mol). The reaction was heated slowly toreflux and allowed to stir for 3 hr. The reaction was cooled to roomtemperature, then diluted with CH₂Cl₂ (1.5 L) and partitioned with H₂O(700 mL). The organic layer was washed with saturated NaHCO₃ (700 mL),dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude materialwas purified by column chromatography (silica gel, 1:1 to 4:1EtOAc:hexanes) and the fractions containing product were combined andconcentrated in vacuo to yield4-(6-amino-5-benzyloxy-pyridin-3-yl)-benzoic acid methyl ester (29.4 g,0.086 mol, 79%). ¹H NMR (CDCl₃, 300 MHz) δ 3.92 (s, 3H), 4.82–4.94 (brs,2H), 5.15 (s, 2H), 7.22 (d, 1H, J, 1.8 Hz), 7.33–7.42 (m, 5H), 7.54 (d,2H, J, 8.6), 7.98 (d, 1H, J, 1.8 Hz), 8.06(d, 2H, J. 8.6 Hz).

3. To a stirring solution of4-(6-amino-5-benzyloxy-pyridin-3-yl)-benzoic acid methyl ester (10.0 g,0.03 mol) in EtOH:H₂O (95:5, 600 mL) was added Pd/C (15.9 g, 0.015 mol)(the reaction was de-gassed under vacuum). The solution was allowed tostir under an H₂ atmosphere for 22 hr. The solution was filtered throughwet celite and the celite washed with EtOH. The filtrate wasconcentrated under vacuum to yield4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoic acid methyl ester (2.3 g, 9.3mmol, 31%). ¹H NMR (MeOD, 300 MHz) δ 3.90 (s, 3H), 7.21 (d, 1H, J, 1.9Hz), 7.62 (d, 2H, J, 8.5 Hz), 7.76 (d, 1H, J, 1.9 Hz), 8.04(d, 2H, J,8.5 Hz).

4. To a stirring solution of 4-(6-amino-5-hydroxy-pyridin-3-yl)-benzoicacid methyl ester (2.3 g, 9.3 mmol) in CH₂Cl₂ (180 mL) was addedN,N-diisopropylethylamine (3.2 mL, 0.019 mol), 4-methyl-benzenesulfonylchloride (2.66 g, 0.014 mol), and PS-DMAP (catalytic amount). Thereaction was stirred at ambient temperature for 6 hr then filtered toremove the resin. The resin was washed with CH₂Cl₂ (3×20 mL), and thecombined fractions were washed with 10% citric acid (100 mL), saturatedNaCl (100 mL), dried (Na₂SO₄) and filtered and concentrated in vacuo.The resulting crude material was purified by column chromatography(silica gel, 100% CH₂Cl₂ to 95:5 CH₂Cl₂:MeOH) and the fractionscontaining the desired product were combined and concentrated in vacuoto yield 4-[6-Amino-5-(toluene-4-sulfonyloxy)-pyridin-3-yl]-benzoic acidmethyl ester (3.3 g, 8.2 mmol, 88%). ¹H NMR (CDCl₃, 300 MHz) δ 2.47 (s,3H), 3.93 (s, 3H), 4.81–4.88 (brs, 2H), 7.36–7.44 (m, 5H), 7.81 (d, 2H,J, 8.3 Hz), 8.05 (d, 2H, J, 8.4 Hz), 8.19–8.27 (brs, 1H).

5. To a stirred solution of1-(3-fluoro-2-trifluoromethyl-phenyl)-ethanol (2.0 g, 9.6 mmol) inanhydrous DMF (500 mL) at 0° C. under a N₂ atmosphere was added NaH(0.38 g, 9.6 mmol). The reaction was allowed to stir for 0.5 hr. Asolution of 4-[6-Amino-5-(toluene-4-sulfonyloxy)-pyridin-3-yl]-benzoicacid methyl ester (3.8 g, 9.6 mmol) in anhydrous DMF (30 mL) was addedto the reaction mixture which was allowed to come to ambient temperatureslowly and stirred for 21 hr at this temperature. The reaction wasdiluted with EtOAc (500 mL) and H₂O (100 mL). The organic layer wasseparated off and the aqueous was further extracted with EtOAc (1×200mL). The organic layers were combined and washed with brine (1×100 mL),dried with Na₂SO₄ and concentrated to dryness under vacuum. The crudemixture was purified by column chromatography (silica gel, 40:60 to70:30 EtOAc:hexanes) and the fractions containing product were combinedand concentrated in vacuo to yield4{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid methyl ester (1.4 g, 3.2 mmol, 34%). ¹H NMR (CDCl₃, 300 MHz) & 1.73(d, 3H, J, 6.2 Hz), 3.91 (s, 3H), 4.87–4.64 (brs, 2H), 5.81 (q, 1H, J,6.1, 6.3 Hz), 6.92 (d, 1H, J, 1.8 Hz), 7.38 (d, 2H, J, 8.5 Hz),7.46–7.66 (m, 3H), 7.93 (d, 1H, J, 1.8 Hz), 8.02 (d, 2H, J, 8.5 Hz).

6. To a stirred solution of4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid methyl ester (1.4 g, 3.2 mmol) in warm IPA (72 mL) was added H₂O(38 mL) containing LiOH (0.68 g, 16.2 mmol). The reaction was heated toreflux for 3.5 hr. The reaction was neutralized and diluted with EtOAc(200 mL) and extracted upon cooling. The organic layer was washed withbrine (50 mL), dried over Na₂SO₄ and concentrated under vacuum to yield4-{6-Amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl)-benzoicacid (1.2 g, 2.8 mmol, 88%). ¹H NMR (MeOD, 300 MHz) δ 1.75 (d, 3H, J,6.2 Hz), 4.88–4.93 (m, 1H), 7.01 (d, 1H, J, 1.8 Hz), 7.39 (d, 2H, J, 8.3Hz), 7.52–7.67 (m, 3H), 7.80 (d, 1H, J, 1.8 Hz), 7.97 (d, 2H, J, 8.3Hz).

7. Preparation of amide compounds: A stirring solution of4-{6-Amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid (50 mg, 0.12 mmol), EDC (27.0 mg, 0.13 mmol) and HOBt (18.0 mg,0.13 mmol) in DMF (2 mL) was added to a two dram vial containing NHR₁R₂(0.12 mmol). The reaction was stirred at room temperature for 18 hr. Thereaction was then diluted with CH₂Cl₂ (3 mL) and partitioned with H₂O.The organic was separated washed with saturated NaCl (1×2 mL) andsaturated NaHCO₃ (1×2 mL). The organic was concentrated to dryness undervacuum. The material was purified using column chromatography (silicagel, 99:1 to 95:5 CH₂Cl₂/MeOH). The fractions containing product wereconcentrated under vacuum to yield amide compounds.

General Procedure 14:

1: To a mixture of 1-(2-chloroethyl)pyrrolidine hydrochloride (200 mg,1.18 mmol) and4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)]-1H-pyrazole (229mg, 1.19 mmol) in DMF (6 mL) was added Cs₂CO₃. The mixture was stirredat room temperature overnight. Water (10 mL) was then added to themixture. The product was extracted with EtOAc (3×10 mL). The combinedextracts were then washed with brine (5×10 mL) to remove the DMF, thendried over Na₂SO₄, and concentrated (142 mg, 41% yield).

2: To a mixture of3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-iodo-pyridin-2-ylamine(200 mg, 0.468 mmol), pinacol boronic ester (1.2 eq), Na₂CO₃ (149 mg,1.41 mmol) in water (1.25 mL), and dimethyl ethyl glycol (3.75 mL, 0.1M)was added Pd(PPh₃)₂Cl₂ (16 mg, 0.020 mmol) in a microwave reactionvessel. The system was degassed and charged with nitrogen. The mixturewas stirred at 160° C. in a microwave apparatus for 15 minutes. Themixture was cooled to room temperature followed by the addition of water(10 mL). The product was extracted with EtOAc (3×20 mL), dried overNa₂SO₄, and concentrated. The crude product was purified by reversephase HPLC with 0.1% TFA in water and acetonitrile.

General Procedure 15:

1: To a solution of 3H-oxazolo[4,5-b]pyridin-2-one (13.6 g, 100 mmol) inacetonitrile (600 mL) and acetic acid (120 mL) was addedN-bromosuccinimide (21.4 g, 120 mmol). The mixture was stirred at roomtemperature for 4 hr and the reaction was quenched with Na₂S₂O₅solution. After evaporation, the residue was partitioned between ethylacetate and water. The organic layer was washed with 2N NaOH solution,brine, and dried over Na₂SO₄. The crude product was purified on a silicagel column to provide 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one (11.5 g,55% yield).

2: 6-Bromo-3H-oxazolo[4,5-b]pyridin-2-one (21.5 g, 100 mmol) wassuspended in NaOH solution (2N, 250 mL, 500 mmol). The mixture wasrefluxed overnight and a clear solution was obtained. After cooling toroom temperature, the reaction solution was neutralized to pH ˜7. A lotof CO₂ was released and also precipitate was observed. The product wasfiltered, washed with water, and dried under high vacuum to provide2-amino-5-bromo-pyridin-3-ol as an off-white solid (17.8 g, 98% yield).

3: To a solution of 2-amino-5-bromo-pyridin-3-ol (358 mg, 1.89 mmol) inDMF (8 mL) was added Cs₂CO₃ (620 mg, 1.89 mmol). The mixture was stirredat room temperature under nitrogen for 1 hr. To the reaction mixture wasadded bromo-compound (0.9 eq) in DMF (5 mL) slowly. The reactionsolution was stirred under nitrogen for five hr, and then partitionedbetween water and ethyl acetate. The organic layer was washed with brinefor three times, dried over MgSO₄. The crude product was purified on asilica gel column eluting with hexane-ethyl acetate (4:1) to provide theproduct with 70%–80% yield.

General Procedure 16 using Example I-488:

1. To a solution of 3-benzyloxy-5-bromo-pyridin-2-ylamine (1 g, 3.58mmol) in dimethylsulfoxide (7 mL) was added sequentiallybis(pinacolato)diborane (1.0 g, 3.94 mmol), potassium acetate (1.05 g,10.7 mmol) [1,1′-bis(diphenylphosphino)ferrocine]dichloropalladium (II),complex with dichloromethane (1:1) (146 mg, 0.18 mmol). The mixture washeated to 80° C. for 16 hr and then cooled to room temperature. Thereaction mixture was diluted with ethyl acetate (50 mL) and filtered.The filtrate was washed with water (2×50 mL) and dried over magnesiumsulfate. Concentration in vacuo yielded the crude boronate as a brownsolid (1.13 g, 97%). ¹H NMR (CDCl₃) δ 1.32 (s, 12H), 5.08 (s, 2H), 5.44(br s, 2H), 7.33–7.42 (m, 6H), 8.03 (s, 1H).

2. An 18 mL reaction vessel was charged with the crude3-benzyloxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine(161 mg, 0.49 mmol), dimethoxyethane (3 mL) and 2-bromopyridine (117 mg,0.74 mmol). To this solution was added(1,1′-bis(diphenylphosphino)ferrocine]dichloropalladium (II), complexwith dichloromethane (1:1) (20 mg, 0.05 mmol) and a 2 M solution ofcesium carbonate in water (0.75 mL, 1.5 mmol). The reactor was warmed to80° C. for 66 hr under a nitrogen atmosphere, then cooled to roomtemperature. The reaction mixture was partitioned between ethyl acetate(5 mL) and water (5 mL). The organic layer was washed with additionalwater (5 mL) and diluted with dimethylformamide (5 mL). Polymer-boundsulfonic acid (0.5 g, 2.1 mmol) was added to the organic solution, andthe resulting mixture was gently agitated for 2 hr. The resin wasfiltered and washed with dimethylformamide, methanol and methylenechloride (3×5 mL each solvent). Then the polymer was reacted with 2 Mammonia in methanol for 1 hr. The resin was filtered and washed withadditional 2 M ammonia in methanol (2×5 mL), and the combined filtrateswere concentrated in vacuo. Purification of the crude product by flashcolumn chromatography yielded 52.2 mg of product as a tan solid (38%yield).

General Procedure 17:

1. To the solution of3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine(procedure 16) (10.0 g, 24.3 mmol) in t-butyl alcohol (50 mL) was addedboc anhydride (5.83 g, 26.7 mmol) and reaction stirred at roomtemperature overnight. Additional boc anhydride (2.25 g, 10.3 mmol) wasadded and reaction stirred overnight again. Material was concentrated toa viscous black oil and used as-is.

2. The crude boronic ester (24.3 mmol theoretical) in THF (150 mL) wasadded to a solution of sodium bicarbonate (16.3 g, 194 mmol) in water(150 mL) and acetone (23 mL). The mixture was cooled to 2° C. and oxone(13.5 g, 21.9 mmol) added slowly, keeping temperature below 8° C. Uponcompletion of addition, reaction was stirred for 5 minutes then quenchedwith sodium bisulfite (14.2 g) in water (28 mL). Ethyl acetate was added(200 mL) and layers separated. Aqueous layer was neutralized with 6N HCland extracted with ethyl acetate (2×200 mL). Combined organics werewashed with water (250 mL) and brine (250 mL), dried (Na₂SO_(r)) andconcentrated to a crude black oil. Silica gel chromatography (ethylacetate/hexane) gave the product as a light brown foam (4.78 g, 49.0%).¹H NMR (CDCl₃) δ 1.48 (s, 9H), 1.74 (d, 3H), 5.75 (q, 1H), 6.61 (d, 1H),76.89 (dt, 1H), 6.94–7.04 (m, 2H), 7.26(d, 1H), 8.19 (bs, 1H). MS m/z401 (M+H)⁺.

3. To cesium carbonate in a 2 dram vial was added[3-(2-Chloro-3,6-difluoro-benzyloxy)-5-hydroxy-pyridin-2-yl]-carbamicacid tert-butyl ester (100 mg, 0.25 mmol) in anhydrous DMF (1 mL)followed by benzyl bromide (89.2 μL, 0.75 mmol). The vial was capped andstirred at 90° C. overnight. Reaction was filtered through a 5 mLChem-Elut tube pre-wetted with water (3.5 mL) and eluted with 1:1 ethylacetate:methylene chloride. After partial concentration, 4N HCl indioxane (1–2 mL) was added and solution concentrated. Reverse phasechromatography (water:acetonitrile, 0.05% TFA) followed bylyophilization, gave the desired product as an off white amorphous solid(25.3 mg, 20.0%) and the bis-addition product as a tan amorphous solid(35.2 mg, 23.7%).

General Procedure 18:

Sodium borohydride (1.5 molar equivalent) was added to solution ofketone (3.89 mmol) in 10 mL of ethanol under a nitrogen atmosphere. Theresulting mixture was stirred at room temperature for 12 hr. The mixturewas then put in an ice bath and quenched with dilute aqueous HCl. Theethanol was evaporated and EtOAc was added to extract the aqueoussolution. The EtOAc layer was dried over Na₂SO₄. The Na₂SO₄ was filteredoff and the filtrated was evaporated to give a oil residue, compound A5.The residue was used without further purification.

3-Hydroxy-2-nitropyridine (1.1 molar equivalent) and triphenylphosphine(1.5 molar equivalent) were added to a solution of compound A5 (1.1mmol) in 10 mL of THF. The reaction mixture was then put in an ice bathand diisopropyl azodicarboxylate (1.5 molar equivalent) was added. Theice bath was removed and the mixture was stirred at room temperature for12 hr. The solvent was evaporated to give a yellow oil residue. Theresidue was purified by silica gel chromatography (eluting EtOAc inhexanes) to give compound A1.

2 M HCl (0.2 mL) was added to solution of compound A1 (0.97 mmol) in 2mL of ethanol. The mixture was then put in an ice bath and Fe powder(365 mg) was added slowly. The reaction was heated to 85° C. for 1 hrand cooled to room temperature. Celite (0.5 g) was added to stir and theresulting mixture was filtered through a bed of celite and rinsed withethanol. The filtrated was evaporated to give a brown oil residue,compound A2. The residue was used without further purification.

Periodic acid (0.25 molar equivalent), iodine (0.5 molar equivalent),H₂O (0.5 mL), and concentrate sulfuric acid (0.03 mL) were added to asolution of compound A2 in 3 mL of acetic acid. The reaction mixture washeated to 85° C. for 5 hr. The reaction mixture was then cooled in anice bath and basified with sat. aq. Na₂CO₃ to a pH of 3–4. Ethyl acetatewas added to extract the aqueous solution. Dry EtOAc layer over Na₂SO₄.The Na₂SO₄ was filtered off and the filtrated was evaporated to give abrown oil residue. The residue was purified by silica gel chromatography(eluting with EtOAc and hexanes) to give desired product, compound A3.

General Procedure 19:

Boronic ester or boronic acid (1.3 molar equivalent) was added to asolution of compound A3 (0.47 mmol) in 5 mL of DME. The mixture wasperged with nitrogen several times and thendichlorobis(triphenylphosphino) palladium (II) (0.05 molar equivalent)was added. Sodium carbonate (3 molar equivalent) in 1 mL of H₂O wasadded to the reaction mixture and the resulting solution was heated to85° C. for 12 hr. Water was added to the reaction mixture to quench thereaction. EtOAc was then added to extract the aqueous solution. DryEtOAc layer over Na₂SO₄. The Na₂SO₄ was filtered off and the filtratedwas evaporated to give a dark brown oil residue. The residue-waspurified by silica gel chromatography (eluting with CH₃OH, CH₂Cl₂,EtOAc, and hexanes) to give desired product, compound A4.

General Procedure 20:

Compound A6 was prepared using general procedure 19.O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium phosphoruspentafloride (HATU) (1.1 molar equivalent), diisopropylethyl amine (5molar equivalent) and amine (1.3 molar equivalent) were added to asolution of compound A6 (0.17 mmol) in 3 mL of DMF under a nitrogenatmosphere. The reaction was allowed to stir at room temperature for 12hr. Saturated NaHCO₃ was added to the reaction mixture to quench thereaction. EtOAc was then added to extract the aqueous solution. DryEtOAc layer over Na₂SO₄. The Na₂SO₄ was filtered off and the filtratewas evaporated to give a brown oil residue. The residue was purified bysilica gel chromatography (eluting with EtOAc and hexanes) to givedesired amide product, compound A7, as a yellow oil.

General Procedure 21:

Acid (16 molar equivalent or less) was added to compound A7 (0.13 mmol)at room temperature. The resulting solution was stirred at roomtemperature or heated to 60° C. for 12 hr. The reaction mixture wasevaporated and the residue was purified by silica gel chromatography(eluting with CH₃OH, EtOAc and CH₂Cl₂) to give desired amide product,compound A8, as a yellowish to white solid.

General Procedure 22:

Compound A9 was prepared using general procedure 19. Di-tert-butyldicarbonate (3 molar equivalent) and 4-(dimethylamino)pyridine (0.14molar equivalent) were-added to a solution of compound A9 (3 mmol) in 20mL of DMF. The reaction mixture was stirred at room temperature for 12hr. Water was added to the reaction mixture to quench the reaction.EtOAc was then added to extract the aqueous solution. Dry EtOAc layerover Na₂SO₄. The Na₂SO₄ was filtered off and the filtrated wasevaporated to give a brown yellow oil residue. The residue was purifiedby silica gel chromatography (eluting with 25→30% EtOAc in hexanes) togive desired product, compound A10 as a yellowish oil (87.8% yield).Ozone was bubbled through a solution of compound A10 in 50 mL of CH₂Cl₂at −78° C. and dimethyl sulfide was added to quench the reaction.Saturated sodium chloride was added to the reaction mixture and EtOAcwas added to extract the aqueous solution. Combined EtOAc layer wasdried over Na₂SO₄. The Na₂SO₄ was filtered off and the filtrated wasevaporated to give a yellow oil residue. The residue was purified bysilica gel chromatography (eluting with 35→40% EtOAc in hexanes) to givedesired product, compound A11 as a yellowish oil (58.4% yield).

General Procedure 23: Reductive Amination

Amine hydrochloride salt (1.2 molar equivalent), sodium acetate (2 molarequivalent to the amine hydrochloride salt) were added to a solution ofcompound A11 (0.45 mmol) in 4 mL of CH₃OH under a nitrogen atmosphere.Molecular sieve (0.5 g) was added to the reaction mixture and thensodium cyanoborohydride (2 molar equivalent) was added. The resultingmixture was stirred at room temperature for 12 hr under a nitrogenatmosphere. The reaction mixture was filtered through a bed of celiteand the filtrate was evaporated and purified by silica gelchromatography (eluting CH₃OH, EtOAc, and CH₂Cl₂) to give desiredproduct, compound A12 as an oil (52.6% yield). Acid (16 molar equivalentor less) was added to compound A12 (0.17 mmol) at room temperature. Theresulting solution was stirred at room temperature or heated to 60° C.for 12 hr. The reaction mixture was evaporated and the residue waspurified by silica gel chromatography (eluting with CH₃OH, EtOAc andCH₂Cl₂) to give desired product, compound A13.

General Procedure 24:

O-phenyldiamines (1.2 molar equivalent) and sodium bisulfite (2:1 molarequivalent) were added to a solution of compound A11 (0.41 mmol) in 5 mLof DMA. The resulting solution was heated to 110° C. for 12 hr. Waterwas added to the reaction mixture to quench the reaction. EtOAc was thenadded to extract the aqueous solution. Dry EtOAc layer over Na₂SO₄. TheNa₂SO₄ was filtered off and the filtrated was evaporated to give a brownyellow oil residue. The residue was purified by silica gelchromatography (eluting with EtOAc in hexanes) to give desired product,compound A14. Acid (16 molar equivalent or less) was added to compoundA14 (0.16 mmol) at room temperature. The resulting solution was stirredat room temperature or heated to 60° C. for 12 hr. The reaction mixturewas evaporated and the residue was purified by silica gel chromatography(eluting with CH₃OH, EtOAc and CH₂Cl₂) to give desired amide product,compound A15.

General Procedure 25:

Di-tert-butyl dicarbonate (3 molar equivalent),4-(dimethylamino)pyridine (0.14 molar equivalent) were added to asolution of compound A3b (2 mmol) in 10 mL of DMF. The reaction mixturewas stirred at room temperature for 12 hr. Water was added to thereaction mixture to quench the reaction. EtOAc was then added to extractthe aqueous solution. Dry EtOAc layer over Na₂SO₄. The Na₂SO₄ wasfiltered off and the filtrated was evaporated to give a brown yellow oilresidue (compound a16). The residue was used without furtherpurification.

Bis(pinacolato)diboron (1.2 molar equivalent) and potassium acetate (3.4molar equivalent) were added to a solution of compound a16 in 4 mL ofDMSO. The mixture was perged with nitrogen several times and thendichlorobis(triphenylphsophino) palladium (II) (0.05 molar equivalent)was added. The resulting solution was heated to 80° C. for 12 hr. Waterwas added to the reaction mixture to quench the reaction. EtOAc was thenadded to extract the aqueous solution. Dry EtOAc layer over Na₂SO₄. TheNa₂SO₄ was filtered off and the filtrated was evaporated to give a darkbrown oil residue. The residue was purified by silica gel chromatography(eluting with 30% EtOAc in hexanes) to give desired product, compoundA17 (76% yield). HCl (5 molar equivalent) was added to a solution ofcompound A17 (0.43 mmol) in 4 mL of CH₂Cl₂. The resulting mixture washeated to 50° C. for 12 hr. Saturated NaHCO₃ was added to the reactionmixture to neutralize the reaction. EtOAc was then added to extract theaqueous solution. Dry EtOAc layer over Na₂SO₄. The Na₂SO₄ was filteredoff and the filtrated was evaporated to give the desired product(compound A18) as a yellow solid (75% yield).

General Procedure 26:

Compound A17 (1.3 molar equivalent) was added to a solution of arylhalide (0.36 mmol) in 3 mL of DME. The mixture was perged with nitrogenseveral times and then dichlorobis(triphenylphsophino) palladium (II)(0.05 molar equivalent) was added. Sodium carbonate (3 molar equivalent)in 0.8 mL of H₂O was added to the reaction mixture and the resultingsolution was heated to 85° C. for 12 hr. Water was added to the reactionmixture to quench the reaction. EtOAc was then added to extract theaqueous solution. Dry EtOAc layer over Na₂SO₄. The Na₂SO₄ was filteredoff and the filtrated was evaporated to give a dark brown oil residue.The residue was purified by silica gel chromatography (eluting withEtOAc in hexanes) to give desired product, compound A19 (74.4% yield).HCl (5 molar equivalent) was added to a solution of compound A19 (0.26mmol) in 10 mL of isopropyl alcohol. The resulting mixture was heated to50° C. for 12 hr. The solvent was evaporated to give the desiredproduct, compound A20.

General Procedure 27:

Compound A18 (1.3 molar equivalent) was added to a solution of arylhalide (0.21 mmol) in 3 mL of DME. The mixture was perged with nitrogenseveral times and then dichlorobis(triphenylphsophino) palladium (II)(0.05 molar equivalent) was added. Sodium carbonate (3 molar equivalent)in 0.6 mL of H₂O was added to the reaction mixture and the resultingsolution was heated to 85° C. for 12 hr. Water was added to the reactionmixture to quench the reaction. EtOAc was then added to extract theaqueous solution. Dry EtOAc layer over Na₂SO₄. The-Na₂SO₄ was filteredoff and the filtrated was evaporated to give a dark brown oil residue.The residue was purified by silica gel chromatography (eluting withCH₃OH, CH₂Cl₂, EtOAc, and hexanes) to give desired product, compoundA21.

General Procedure 28:

Amine (1.5 molar equivalent) and K₂CO₃ (1.5 molar equivalent) were addedto a solution of 4-halobenzyl halide (1.0 molar equivalent) in 2 mL oftoluene. The resulting mixture was microwaved using Smithsynthesizer(150° C., 1 hr). Water was added to the reaction mixture to quench thereaction. EtOAc was then added to extract the aqueous solution. DryEtOAc layer over Na₂SO₄. The Na₂SO₄ was filtered off and the filtratedwas evaporated to give the desired product, compound A23. The residuewas used in procedure 11 without further purification to synthesizecompound A22.

General Procedure 29:

Amine (1.2 molar equivalent) and diisopropylamine (5 molar equivalent)were added to a solution of 4-bromobenzenesulfonyl chloride (0.77 mmol)in 5 mL of CHCl₃ under a nitrogen atmosphere. The resulting mixture wasstirred at room temperature for 4 hr. Water was added to the reactionmixture to quench the reaction. EtOAc was then added to extract theaqueous solution. Dry EtOAc layer over Na₂SO₄. The Na₂SO₄ was filteredoff and the filtrated was evaporated to give the desired product,compound A25. The residue was used in procedure 11 without furtherpurification to synthesize compound A24.

General Procedure 30:

Boronic ester or boronic acid (1.2 molar equivalent) was added to asolution of 1-chloro-4-iodobenzene (0.84 mmol) in 10 mL of ethyleneglycol diemthylether (DME) under a nitrogen atmosphere. The mixture wasperged with nitrogen several times and thendichlorobis(triphenylphsophino) palladium (II) (0.05 molar equivalent)was added. Sodium carbonate (3 molar equivalent) in 1.8 mL of H₂O wasadded to the reaction mixture and the resulting solution was heated to85° C. for 12 hr. Water was added to the reaction mixture to quench thereaction. EtOAc was then added to extract the aqueous solution. DryEtOAc layer over Na₂SO₄. The Na₂SO₄ was filtered off and the filtratedwas evaporated to give a dark brown oil residue. The residue waspurified by silica gel chromatography (eluting with CH₃OH, CH₂Cl₂,EtOAc, and hexanes) to give desired product, compound A27. Compound A27was used in procedure 11 to synthesize compound A26.

General Procedure 31 for Chiral Separation of Racemates:

The racemic sample was purified using preparative supercritical fluidchromatography SFC-MS. The purification conditions were:column-Chiralpak AD-H, 250×21 mm, 5 micron, 100A column (Column#:ADH0CJ-C1003); column temperature 350° C.; mobile phase 35%-methanol(with 0.1% isopropylamine)-modified CO₂; preparative flow rate 52mL/min; isobaric pressure at 120 bar. The specific chirality of theisomers was not definitively determined.

General Procedure 32: using Example I-617

To a mixture of4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester (100 mg, 0.23 mmol) and1-(1-bromo-ethyl)-3-trifluoromethyl-benzene (64 mg, 0.25 mmol) in DMF (2ml) was added NaH (12 mg, 0.47 mmol) at 0° C. The mixture was stirredovernight. LCMS showed that the reaction was completed, DMF and waterwere removed. TFA (2 mL) was added to the residue and stirred at roomtemperature for 3 hr. TFA was removed followed by addition of methanol.The residue was purified by prep-HPLC to afford(4-{6-Amino-5-[1-(3-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone(30 mg, yield 25.7%).

General Procedure 33: Using Example I-616

To a mixture of4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester (50 mg, 0.12 mmol) and1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol) in DMF (2ml) was added 2 M Cs₂CO₃ (0.18 mL, 0.35 mmol), followed by water (0.5mL), the mixture was stirred overnight then heated at 70° C. for 8 hr,LCMS showed that the reaction was completed. The DMF and water wereremoved. TFA (2 mL was added to the residue and stirred at roomtemperature for 3 hr. The TFA was removed, followed by addition ofmethanol. The residue was purified by prep-HPLC to afford(4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl)-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone(20 mg, yield 34.2%).

Procedure 34: using Example I-624

To a mixture of(2R,6S)-4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester (100 mg, 0.23 mmol) and1-bromomethyl-2-methyl-benzene (47 mg, 0.25 mmol) in DMF(2 mL) was added2 M Cs₂CO₃ (0.35 mL, 0.7 mmol) followed by water (0.5 mL). The mixturewas stirred at room temperature overnight. LCMS showed the reaction wascompleted, DMF was removed, followed by addition of 4 N HCl in dioxane(2 mL) and the reaction was stirred at room temperature for 3 hr. Thevolatiles were removed followed by addition of methanol. This solutionwas purified by prep-HPLC to afford{4-[6-Amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone(47 mg, yield 46.6%).

Procedure 35: using Example I-635

To a mixture of[3-(4-iodo-benzoyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-carbamic acidtert-butyl ester (100 mg, 0.234 mmol) and3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine(100 mg, 0.234 mmol) in DME (2 mL) was added Pd(dppf)₂Cl₂.CH₂Cl₂ (10 mg,0.012 mmol) and Cs₂CO₃ (351 mg, 0.702 mmol). The mixture was bubbledwith nitrogen for 10 min then microwaved at 150° C. for 30 min. LCMSchecked that the reaction was completed. The crude reaction mixture wasdiluted with ethyl acetate followed by washings with water and brine.The solution was dried over MgSO₄. Purification by prep-HPLC afforded asolid. The solid was stirred with 4 N HCl/dioxane (3 mL) for 3 hr atroom temperature. Removal of the volatiles led to a residue that waspurified by prep-HPLC to afford(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanone(30 mg, yield 26%).

Procedure 36: using Example I-636

To a mixture of6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ol(78 mg, 0.20 mmol), triphenyphosphine (63 mg, 0.24 mmol) and2-morpholin-4-yl-ethanol (0.026 mL, 0.22 mmol) was added DEAD (0.034 mL,0.22 mmol). After stirring overnight more PPh₃ (63 mg, 0.24 mmol) andmore DEAD (0.034 mL, 0.22 mmol) were added. After several hours, morealcohol (0.026 mL, 0.22 mmol) was added. After several more hours, morePPh₃ (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol) were added.After stirring overnight, the mixture was partitioned betweendichloromethane and half-saturated brine. The phases were separated andthe aqueous phase was extracted with dichloromethane. The combinedorganic phases were dried over Na₂SO₄ and concentrated by rotaryevaporation. The residue was purified by silica gel chromatography usinggradient elution of dichloromethane, methanol to afford5-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-6′-(2-morpholin-4-yl-ethoxy)-[3,3′]bipyridinyl-6-ylamine(53 mg, 53%).

Procedure 37: using Example I-650

3-(2,6-Dichloro-3-fluoro-benzyloxy)-5-thiazol-2-yl-pyridin-2-ylamine: Toa microwave tube equipped with a stir bar was added the iodo-pyridylstarting material (300 mg, 0.702 mmol), tetrakis(triphenylphosphine)palladium (0) (40 mg, 5 mol %) and tetrahydrofuran (anhydrous, 6 mL).The vial was capped and purged with nitrogen for 5 minutes.2-Thiazolylzinc bromide (0.5 M in THF, 1.4 mmol, 2.8 mL) was then addedvia syringe. The vial was heated to 120° C. in the microwave for 10minutes. TLC (1:1 ethyl actetate:methylene chloride) showed a largeamount of starting material remaining. Additional 2-thiazolylzincbromide (0.5 M in THF, 500 μL) was added and the vial was heated to 120°C. in the microwave for 20 minutes. TLC (1:1 ethyl actetate:methylenechloride) showed a large amount of starting material still remaining.Additional 2-thiazolylzinc bromide (0.5 M in THF, 500 μL) was added andthe vial was heated to 120° C. in the microwave for 60 minutes. TLC (1:1ethyl actetate:methylene chloride) still showed a large amount ofstarting material still remaining but also had become very messy. Thevial contents were poured into a sat. NH₄Cl solution (10 mL) and thissolution extracted with ethyl acetate (2×30 mL). The combined ethylacetate layers were dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was loaded onto a 10 g prepacked silica gelcolumn and 1:1 ethyl acetate:methylene chloride used to elute thedesired product. (40 mg, 15%).

Procedure 38: using Example I-652

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-methyl-1H-imidazol-2-yl)-pyridin-2-ylamine:N-methyl imidazole (92 mg, 1.1 mmol) was dissolved in tetrahydrofuran(anhydrous, 4 mL) in a 50 mL round bottom flask. The flask was cooledwith a dry-ice/acetone bath under nitrogen atmosphere. N-butyl lithium(2.5 M, 562 μL, 1.4 mmol) was added via syringe in 100 μL portions over5 minutes. The reaction was stirred at −70° C. for 30 minutes. Solidzinc chloride (anhydrous, 383 mg, 2.8 mmol) was added and the reactionstirred for 15 minutes. The ice bath was then removed and the reactionallowed to warm to room temperature. Once all of the zinc chloride wasin solution-and the reaction at room temperature, iodo scaffold (400 mg,0.936 mmol) was added in tetrahydrofuran (anhydrous, 4 mL), followed bytetrakis(triphenylphosphine) palladium (0) (108 mg, 10 mol %) and thereaction heated to reflux. The reaction was monitored by LC/MS until allof the starting iodo scaffold was consumed. The reaction was allowed tocool and then diluted with a sat. NH₄Cl solution (20 mL). This solutionwas extracted with ethyl acetate (2×50 mL). The combined ethyl acetatelayers were dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was loaded onto a 10 g prepacked silica gel column and 10%methanol:ethyl acetate was used to elute the desired product (25 mg,7%).

General Procedure 39: using Example I-657

To 6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-nicotinonitrile(400 mg, 1.23 mmol) in 70 mL dry methanol at 0° C. was bubbled HCl gasfor 3 minutes. Stirred overnight at 3° C. Removed volatiles and washedthe solids with diethyl ether to yield quanitatively the imidate. To 200mg of the imidate in 4 mL methanol at 0° C. was added 2N methylamine inTHF (837 μL). Let stir at 0° C. for about 1 hr then let warm to rtovernight. The volatiles were removed and the residue waschromatographed with 10–20% methanol/dichloromethane to yield 70 mg ofproduct.

General Procedure 40:

1. 6-Nitro-5-hydroxynicotinic acid (B2): To a solution of5-hydroxynicotinic acid (B₁) (7.0 g, 50 mmol) in concentrated H₂SO₄ wasadded 9 mL of fuming HNO₃ (90%) (9 mL). The reaction mixture was stirredat 55–60° C. in a sealed tube for four days. The mixture was then pouredinto ice and the pH was adjusted to 3 with 50% NaOH. MgSO₄ was added tosaturate the aqueous mixture, which was then extracted with isopropylalcohol (4×45 mL). After the removal of isopropyl alcohol under reducedpressure, 5.93 9 (64% yield) of B2 was obtained as a yellow solid. MS(APCI), (M+H)⁺185. ¹HNMR (DMSO-d6) δ 8.01 (d, 1H, Ar—H), 8.41(d, 1H,Ar—H).

2. 2,6-Dichlorobenzyl-6-nitro-5-[(2,6-dichlorobenzyl)oxy]nicotinate(B3): 6-nitro-5-hydroxynicotinic acid (B2) (3.4 g, 18.5 mmol),2,6-dichlorobenzyl bromide (8.88–9, 37 mmol), DIPEA (5.5 g, 42.5 mmol)were dissolved in DMF (25 mL) in a 250 mL round bottomed flask and thereaction was stirred at room temperature for 4.5 hr and thenconcentrated under reduced pressure. The resulting mixture was pouredinto ice and the filtered. The solid collected was dried under reducedpressure to give 4.25 g (46% yield) of B3 MS (APCI) (M+H)+503. ¹HNMR(DMSO-d6) δ 5.47 (s, 2H, ArCH₂O), 5.71 (s, 2H, ArCH₂O), 7.24–7.43 (m,6H, Ar—H), 8.26(d, 1H, Ar—H), 8.66(d, 1H, Ar—H).

3. 2,6-Dichlorobenzyl-6-amino-5-[(2,6-dichlorobenzyl)oxy]nicotinate(B4): A mixture of2,6-dichlorobenzyl-6-nitro-5-[(2,6-dichlorobenzyl)oxy]nicotinate (B3)(5.5 g, 10.96 mmol), iron powder (0.92 g, 16.43 mmol), glacial aceticacid (20 mL) and methanol (17 mL) was stirred at 85° C. for three hr.The reaction mixture was concentrated to near dryness, and ammoniumhydroxide (30%) was added to neutralize the mixture. Minimum amount ofDMF was added to dissolve the reaction mixture, which was purified byflash column chromatograph (eluent: EtOAc-EtOH, 9:1) to give 4.5 g (87%)of B4 as a pale yellow solid. MS (APCI) (M+H)⁺473.

4. 6-Amino-5-[(2,6-dichlorobenzyl)oxy]nicotinic acid (B5): A mixture of2,6-dichlorobenzyl-6-amino-5-[(2,6-dichlorobenzyl)oxy]nicotinate (B4)(3.5 g, 7.4 mmol), lithium hydroxide (0.41 g, 17 mmol), water (22 mL)and methanol (30 mL) was stirred and reflux at 85° C. for 5 hr. Themixture was concentrated to dryness under reduced pressure. Theresulting residue was dissolved in water, extracted with a mixture ofEt₂O/hexane (1:1, 4×25 mL), neutralized with 1N HCl to form whiteprecipitation, which was filtered and dried under reduced pressure toprovide 1.83 grams (79%) of B5 as a white solid. MS (APCI) (M+H)+313.¹HNMR (DMSO-d6) 3 5.26 (s, 2H, ArCH₂O), 6.37 (s, 2H, NH₂), 7.43–7.48 (t,1H, Ar—H), 7.54 (s, 2H, Ar—H), 7.56 (s, 1H, Ar—H), 8.18 (s, 1H, Ar—H).

To an array of 400 μL of 0.2 M solution of different amines in DMF in a96-well plate was added 400 μL (0.2 M in DMF) of4-[6-amino-5-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-3-yl]-benzoicacid, 80 μL of triethylamine (1 M in DMF) and 160 μL of HATU (0.5 M inDMF) and the reactions were stirred at 70° C. for 2 hr. The solvent wasremoved using the SpeedVac apparatus and the crude reaction mixtureswere redissolved in DMSO and transferred using a liquid handler to a 1mL 96-well plate to give a final theoretical concentration of ˜10 mM.The reactions were analyzed and positive product identification was madeusing LC/MS. The mother stock solution was diluted to 50 nM and assayedfor percent inhibition of c-MET at 50 nM.

General Procedure 41:

To an array of 400 mL of 0.2 M solution of different amines in DMF in a96-well plate was added 400 μL (0.2 M in DMF) of6-Amino-5-[(2,6-dichlorobenzyl)oxy]nicotinic acid, 80 μL oftriethylamine (1 M in DMF) and 160 μL of HATU (0.5 M in DMF) and thereactions were stirred at 70° C. for 2 hr. The solvent was removed usingthe SpeedVac apparatus and the crude reaction mixtures were redissolvedin DMSO and transferred using a liquid handler to a 1 mL 96-well plateto give a final theoretical concentration of ˜10 mM. The reactions wereanalyzed and positive product identification was made using LC/MS. Themother stock solution was diluted to 1 μM and assayed

General Procedure 42:

[4-(6-Amino-5-hydroxy-pyridin-3-yl)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone:To a solution of[4-(6-Amino-5-benzyloxy-pyridin-3-yl)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone(3.67 g, 8.1 mmol) in 100 ml ethanol was added 25 ml cyclohexane and 367mg palladium black. Reluxed overnight. The solution was filtered and thevolatiles were removed. To the residue was added 60 mL of MeOH, 20 mLcyclohexene and 350 mg Pd black. Refluxed-overnight. Filtered andremoved volatiles, resuspended in methanol, added 350 mg Pd black andhydrogenated at 1 atm overnight (pressure reactors all busy). Filteredand isolated 3.0 grams of a solid foam. ¹H NMR (400 MHz, DMSO-D6) δ ppm7.82 (d, J=2.02 Hz, 1H) 7.58 (d, J=8.34 Hz, 2H) 7.41 (d, J=8.34 Hz, 2H)7.12 (d, J=2.02 Hz, 1H) 5.74 (s, 2H) 3.33 (s, 5H) 3.08 (s, 2H) 1.95 (m,8H) 1.49 (s, 2H). LC/MS(APCI) 367 m/e (M+1).

To an array of 10×75 mm test tubes were added[4-(6-Amino-5-hydroxy-pyridin-3-yl)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone(0.2 M in DMF, 80 μmol, 1.0 eq.), Cs₂CO₃ (2 M, 160 μmol, 2.0 equiv) anddifferent alkyl halides (0.2 M in DMF, 88 μmol, 1.1 eq.). The reactionswere stirred at room temperature overnight. In order to separate theinorganic salts, the resulting suspension was evaporated and DMF (625μL) was added. After agitation, the mixture was centrifuged to settlethe solid residue, and the supernatant was transferred to a new 10×75 mmtest tube. The reactions were analyzed and positive productidentification was made using LC/MS. The mother stock solution wasdiluted to 1 μM and assayed.

General Procedure 43:

(2R,6S)-4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester: See general procedure IG. Yield 83.5%. ¹H NMR(400 MHz, DMSO-D6) δppm 7.81 (d, J=2.27 Hz, 1H) 7.57 (d, J=8.34 Hz, 2H)7.41 (d, J=8.34 Hz, 2H) 7.12 (d, J=2.02 Hz, 1H) 5.70

(s, 2H) 4.07 (s, 2H) 3.31 (s, 3H) 1.39 (s, 10H) 1.03–1.14 (m, 7H)

To an array of 10×75 mm test tubes were added[4-(6-Amino-5-hydroxy-pyridin-3-yl)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone(0.2 M in DMF, 80 μmol, 1.0 eq.), Cs₂CO₃ (2 M, 160 μmol, 2.0 equiv) anddifferent alkyl halides (0.2 M in DMF, 88 μmol, 1.1 eq.). The reactionswere stirred at room temperature overnight. In order to separate theinorganic salts, the resulting suspension was evaporated and DMF (625μL) was added. After stirring, the mixture was centrifuged to settle thesolid residue, and the supernatant was transferred to a new 10×75 mmtest tube. The solid residues were extracted with more DMF (400 μL) andthe extracts were combined with the first organic layer. The DMF wasevaporated, and HCl (4 M in dioxane, 2.5 mmol, 31 eq.) was added to thereaction mixture in the receiving test tube. The reaction mixture wasstirred at room temperature for 3 hr. The reactions were analyzed andpositive product identification was made using LC/MS. The mother stocksolution was diluted to 1 μM and assayed.

Example I(a)

1. To a stirred solution of Cs₂CO₃ (11.63 g, 35.69 mmol) in DMF (180 mL)under a N₂ atmosphere containing 3-hydroxy-4-nitro-pyridine (5 g, 35.69mmol) was added 2,6-dichlorobenzyl bromide (8.56 g, 35.69 mmol). Themixture was stirred for 6 h at ambient temperature. The reaction wasthen diluted with EtOAc (400 mL) and partitioned with H₂O (100 mL). Theaqueous layer was extracted with EtOAc (2×50 mL). The organic layerswere then combined and washed with H₂O (2×50 mL) and brine (1×50 mL).The organics were dried over Na₂SO₄, filtered and concentrated todryness under vacuum to yield3-(2,6-dichloro-benzyloxy)-2-nitro-pyridine (10.5 g, 98.4%) as a whitesolid.

2. To a stirred mixture of AcOH (650 mL) and EtOH (500 mL) was suspended3-(2,6-dichloro-benzyloxy)-2-nitro-pyridine (37.4 g, 0.11 mol) and ironchips (69.4 g, 0.11 mol). The reaction was heated slowly to reflux andallowed to stir for 1 hr. The reaction was cooled to room temperaturethen filtered through a pad of celite. The resulting filtrate wasneutralized with conc. NH₄OH (600 mL) and then extracted with EtOAc(3×500 mL). The combined organic extracts were washed with saturatedNaHCO₃ (2×100 mL), H₂O (2×100 mL) and brine (1×100 mL) then dried(Na₂SO₄), filtered and concentrated to dryness under vacuum to yield3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (32.4 g, 0.11 mol, 99%) asa light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.56 (m, 3H), 7.46(dd, 2H), 7.36 (d, 1H), 6.62 (dd, 1H), 6.18 (br s, 2H, NH₂), 5.24 (s,2H); MS m/z 270 [M+1].

3. A stirring solution of 3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine(32.4 g, 0.11 mol) in acetonitrile was cooled to 0° C. using an icebath. To this solution was added N-bromosuccinimide (19.5 g, 0.11 mol)portionwise. The reaction was stirred at 0° C. for 15 min. The reactionwas concentrated to dryness under vacuum. The resulting dark oil wasdissolved in EtOAc (500 mL) and partitioned with H₂O (250 mL). Theorganic was then washed with sat'd NaHCO₃ (2×200 mL) and brine (1×200mL). Activated charcoal was added to the organic layer and warmed toreflux. The solution was then cooled to room temperature and filteredthrough a pad of celite. The organic was then concentrated to drynessunder vacuum to one third the original volume. The solids were thenfiltered off to yield5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (22.0 g, 0.07 mol,64%) as a tan solid. The remaining filtrate was concentrated undervacuum to yield crude5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (12.1 g, 0.04 mol,35%) as a brown solid.

Example I(b)

3-Benzyloxy-5-bromo-pyridin-2-ylamine was prepared following procedure 1from 3-benzyloxy-pyridin-2-ylamine as a tan solid in 65% yield.

Example I(c)

5-Bromo-3-(2,6-difluoro-benzyloxy)-pyridin-2-ylamine was preparedfollowing procedure 1. 3-(2,6-difluoro-benzyloxy)-2-nitro-pyridine wasprepared in 99% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (m, 2H), 7.79(dd, 1H), 7.52 (m, 1H), 7.16 (m, 2H), 5.37 (s, 2H); MS m/z 266 [M+].3(2,6-Difluoro-benzyloxy)-pyridin-2-ylamine was prepared in 100% yield.¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 2H), 7.64 (dd, 1H), 7.57 (m, 2H),6.84 (dd, 1H), 5.24 (s, 2H); MS m/z 237 [M+1].5-Bromo-3-(2,6-difluoro-benzyloxy)-pyridin-2-ylamine was prepared in 91%yield.

Example I(d)

5-Bromo-3-(2-bromo-benzyloxy)-pyridin-2-ylamine was prepared followingprocedure 1. 3-(2-bromo-benzyloxy)-2-nitro-pyridine intermediate wasprepared in 99% yield as a white solid.3-(2-bromo-benzyloxy)-pyridin-2-ylamine was prepared in 100% yield as asolid. 5-Bromo-3-(2-bromo-benzyloxy)-pyridin-2-ylamine was obtained in37% yield as a tan solid.

Example I(e)

5-Bromo-3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine was preparedfollowing procedure 1. 3-(2-chloro-6-fluoro-benzyloxy)-2-nitro-pyridinewas prepared in 90% yield as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.15 (m, 2H), 7.80 (m, 1H), 7.50 (m, 1H), 7.40 (m, 1H), 7.30(m, 1H), 5.39 (s, 2H). 3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylaminewas prepared in 88% yield as a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.70–7.15 (m, 5H), 6.45 (m, 1H), 5.45 (br s, 2H), 5.06 (s, 2H).5-Bromo-3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine was preparedin 81% yield.

Example I(f)

5-Bromo-3-(2-chloro-4-fluoro-benzyloxy)-pyridin-2-ylamine was preparedfollowing procedure 1. 3-(2-chloro-4-fluoro-benzyloxy)-2-nitro-pyridinewas prepared in 91% yield as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.08 (m, 2H), 7.75 (m, 1H), 7.63 (m, 1H), 7.55 (m, 1H), 7.25(m, 1H), 5.45 (s, 2H). 3-(2-chloro-4-fluoro-benzyloxy)-pyridin-2-ylaminewas prepared in 100% yield as a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.70 (m, 2H), 7.47 (m, 1H), 7.20 (m, 1H), 7.08 (m, 1H), 6.45 (m, 1H),5.62 (br s, 2H), 5.08 (s, 2H).5-Bromo-3-(2-chloro-4-fluoro-benzyloxy)-pyridin-2-ylamine was preparedin 63% yield.

Example I(g)

5-Bromo-3-(2,4-dichloro-benzyloxy)-pyridin-2-ylamine was preparedfollowing procedure 1. 3-(2,4-Dichloro-benzyloxy)-2-nitro-pyridine wasprepared in 96% yield as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ8.05–7.50 (m, 6H), 5.39 (s, 2H); MS (m/z) 299 (M+1).3-(2,4-Dichloro-benzyloxy)-pyridin-2-ylamine was prepared in 98% yieldas a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.65–6.25 (m, 6H), 5.85 (brs, 2H), 5.06 (s, 2H).5-Bromo-3-(2,4-dichloro-benzyloxy)-pyridin-2-ylamine was prepared in 65%yield.

Example I(h)

2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile was preparedfollowing procedure 1. 2-(2-Nitro-pyridin-3-yloxymethyl)-benzonitrilewas prepared in 91% yield as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.15–7.55 (m, 1H), 5.50 (s, 2H).2-(2-Amino-pyridin-3-yloxymethyl)-benzonitrile was prepared in 86% yieldas a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.95–6.45 (m, 7H), 5.65 (brs, 2H), 5.20 (s, 2H).2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile was prepared in77% yield.

Example I(i)

5-Bromo-3-(2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine was preparedfollowing procedure 1. 3-(2-trifluoromethyl-benzyloxy)-2-nitro-pyridinewas prepared in 92% yield as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.05–7.58 (m, 7H), 5.45 (s, 2H).3-(2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine was prepared in 80%yield as a tan solid.5-Bromo-3-(2-chloro-4-fluoro-benzyloxy)-pyridin-2-ylamine was preparedin 43% yield as a solid.

Example I(j)

5-Bromo-3-(4-tert-butyl-benzyloxy)-pyridin-2-ylamine was preparedfollowing procedure 1. 3-(4-tert-butyl-benzyloxy)-2-nitro-pyridine wasprepared in 80% yield as an oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.10–7.30(m, 7H), 5.30 (s, 2H), 1.25 (s, 9H).3-(4-tert-Butyl-benzyloxy)-pyridin-2-ylamine was prepared in 100% yieldas a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.45–6.25 (m, 7H), 5.58 (brs, 2H), 5.05 (s, 2H), 1.25 (s, 9H).5-Bromo-3-(4-tert-butyl-benzyloxy)-pyridin-2-ylamine was prepared in 55%yield as a solid.

Example I(k)

5-Bromo-3-(2-chloro-benzyloxy)-pyridin-2-ylamine was prepared followingprocedure 1. 3-(2-Chloro-benzyloxy)-2-nitro-pyridine was prepared in 89%yield as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.10–7.40 (m,7H), 5.40 (s, 2H). 3-(2-Chloro-benzyloxy)-pyridin-2-ylamine was preparedin 100% yield as a tan solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.65–6.45 (m,7H), 5.62 (br s, 2H), 5.10 (s, 2H).5-Bromo-3-(2-chloro-benzyloxy)-pyridin-2-ylamine was prepared in 22%yield as a solid.

Example I(l)

5-Bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine wasprepared following procedure 1.3-(2-chloro-3,6-difluoro-benzyloxy)-2-nitro-pyridine intermediate wasprepared in 99% yield as an off white solid. ¹H NMR (CDCl₃, 300 MHz)δ5.31 (s, 2H), 7.02–7.09 (dt, 1H, J, 4, 8), 7.17–7.23 (dt, 1H, J, 4.5,8.4), 7.54–7.58 (dd. 1H, J, 4.5, 8.4), 7.71–7.68 (dd, 1H, J, 1.21, 8.4),8.14–8.16 (dd, 1H, J, 1.23, 4.5).3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine was prepared in100% yield as a light yellow solid. ¹H NMR (CDCl₃, 300 MHz) δ 4.6–4.8(brs, 2H), 5.2 (s, 2H), 7.0–7.08 (dt, 1H, J, 4.1, 9.0), 7.09–7.12 (dd,1H, J, 1.0, 7.8), 7.15–7.22 (dt, 1H, J, 4.8, 8.0), 7.69–7.71 (dd, 1H, J,1.2, 5.1). 5-Bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylaminewas obtained in 64% yield as a tan solid.

Example I(m)

5-Bromo-3-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine wasprepared following procedure 1 starting from 3-hydroxy-4-nitro-pyridineand 1-bromomethyl-3-fluoro-2-trifluoromethyl-benzene.

Example I(n)

1. 2,6-Dichloro-3-fluoroacetophenone (15 g, 0.072 mol) was stirred inTHF (150 mL, 0.5 M) at 0° C. using an ice bath for 10 min. Lithiumaluminum hydride (2.75 g, 0.072 mol) was slowly added. The reaction wasstirred at ambient temperature for 3 hr. The reaction was cooled in icebath, and water (3 mL) was added drop wisely followed by adding 15% NaOH(3 mL) slowly. The mixture was stirred at ambient temperature for 30min. 15% NaOH (9 mL), MgSO₄ were added arid the mixture filtered toremove solids. The solids were washed with THF (50 mL) and the filtratewas concentrated to give 1-(2,6-Dichloro-3-fluoro-phenyl)-ethanol (14.8gm, 95% yield) as a yellow oil. ¹H-NMR (400 MHz, DMSO-d₆) δ 1.45 (d,3H), 5.42 (m, 2H), 7.32 (m, 1H), 7.42 (m, 1H).

2. To a stirred solution of triphenyl phosphine (8.2 g, 0.03 mol) andDEAD (13.65 mL of a 40% solution in toluene) in THF (200 mL) at 0° C.was added a solution of 1-(2,6-dichloro-3-fluoro-phenyl)-ethanol (4.55g, 0.021 mol) and 3-hydroxy-nitropyridine (3.35 g, 0.023 mol) in THF(200 mL). The resulting bright orange solution was stirred under anitrogen atmosphere at ambient temperature for 4 hours at which pointall starting materials had been consumed. The solvent was removed, andthe crude material was dry loaded onto silica gel, and eluted with ethylacetate-hexanes (20:80) to yield3-(2,6-dichloro-3-fluoro-benzyloxy)-2-nitro-pyridine (6.21 g, 0.021 mol,98%) as a pink solid. ¹H NMR (CDCl₃, 300 MHz) δ1.8–1.85 (d, 3H),6.0–6.15 (q, 1H), 7.0–7.1 (t, 1H), 7.2–7.21 (d, 1H), 7.25–7.5 (m, 2H),8.0–8.05 (d, 1H).

3. 3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine was preparedfollowing procedure 1. To a stirred mixture of AcOH (650 mL) and EtOH(500 mL) was suspended3-(2,6-dichloro-3-fluoro-benzyloxy)-2-nitro-pyridine (9.43 g, 0.028 mol)and iron chips (15.7 g, 0.28 mol). The reaction was heated slowly toreflux and allowed to stir for 1 hr. The reaction was cooled to roomtemperature then diethyl ether (500 mL) and water (500 mL) was added.The solution was carefully neutralized by the addition of sodiumcarbonate. The combined organic extracts were washed with sat'd NaHCO₃(2×100 mL), H₂O (2×100 mL) and brine (1×100 mL) then dried (Na₂SO₄),filtered and concentrated to dryness under vacuum to yield3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (9.04 g, 0.027mol, 99%) as a light pink solid. ¹H NMR (CDCl₃, 300 MHz) δ1.8–1.85 (d,3H), 4.9–5.2 (brs; 2H), 6.7–6.84 (q, 1H), 7.0–7.1 (m, 1H), 7.2–7.3 (m,1H), 7.6–7.7 (m, 1H).

4. 5-bromo-3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine wasprepared following procedure 1. A stirring solution of3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (9.07 g, 0.03 mol)in acetonitrile was cooled to 0° C. using an ice bath. To this solutionwas added NBS (5.33 g, 0.03 mol) portionwise. The reaction was stirredat 0° C. for 15 min. The reaction was concentrated to dryness undervacuum. The resulting dark oil was dissolved in EtOAc (500 mL), andpurified via silica gel chromatography. The solvents were then removedin vacuo to yield5-bromo-3-(2,6-dichloro-3-fluoro-benzyloxy)-pyridin-2-ylamine (5.8 g,0.015 mol, 51%) as a white crystaline solid.

Example I(o)

1. 2-Chloro-3,6-difluorobenzaldehyde (1.0 molar equivalent) wasdissolved in THF (0.2 M) and stirred at 0° C. for 5 min. Thecorresponding methylmagnesium chloride solution (1.1 molar equivalent)was added. The reaction was warmed up gradually to ambient temperatureand stirred for 2 hr. Methanol, and 1 N HCl was added to the mixture anddiluted with ethyl acetate. The mixture was washed with water, brine,dried over MgSO₄, filtered, and concentrated to give1-(2-chloro-3,6-difluoro-phenyl)-ethanol as oil. ¹H NMR (400 MHz,DMSO-d₆) δ 1.42 (d, 3H), 5.21 (m, 1H), 5.42 (m, 1H), 7.09 (m, 1H), 7.18(m, 1H).

2. 5-bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-2-ylaminewas prepared following the same procedure as Example I(n) starting from1-(2-chloro-3,6-difluoro-phenyl)-ethanol and 3-hydroxy-nitropyridine.

Example II(a)

To an ice cooled solution of (2,6-dichloro-phenyl)-methanol (5 g, 28.2mmol) in anhydrous tetrahydrofuran (200 mL) was added sodium hydride(1.13 g, 28.2 mmol, 60% disp.) slowly under nitrogen atmosphere. Afterstirring for 30 minutes, 3,5-dibromo-pyrazin-2-ylamine (7.08 g, 28.2mmol) in anhydrous tetrahydrofuran (50 mL) was added via an additionfunnel. Once the addition was complete the ice bath was removed and thereaction was refluxed under nitrogen and monitored by reversed phaseHPLC. After 18 hr HPLC showed that the majority of the starting3,5-dibromo-pyrazin-2-ylamine had been consumed and the reaction wasallowed to cool to room temperature. The reaction mixture wasconcentrated in vacuum until 50 mL remained. The mixture was dilutedwith ethyl acetate (200 mL) and extracted with 50% brine (2×200 mL). Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated in vacuum. The crude product was purified using a silicagel column eluting with 1:1 ethyl acetate/dichloromethane to yield5-bromo-3-(2,6-dichloro-benzyloxy)-pyrazin-2-ylamine as a white solid(8.17 g, 83% yield).

Example II(b)

5-Bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylamine wasprepared following procedure 2 from(2-chloro-3,6-difluoro-phenyl)-methanol and3,5-dibromo-pyrazin-2-ylamine.

Example II(c)

1. 2-Chloro-3,6-difluorobenzaldehyde (1.0 molar equivalent) wasdissolved in THF (0.2 M) and stirred at 0° C. for 5 min. Thecorresponding methylmagnesium chloride solution (1.1 molar equivalent)was added The reaction was warmed up gradually to ambient temperatureand stirred for 2 hr. Methanol and 1N HCl were added to the mixture anddiluted with ethyl_acetate. The mixture was washed with water, brine,dried over MgSO₄, filtered, and concentrated to give1-(2-chloro-3,6-difluoro-phenyl)-ethanol as oil. ¹H NMR (400 MHz,DMSO-d₆) δ 1.42 (d, 3H), 5.21 (m, 1H), 5.42 (m, 1H), 7.09 (m, 1H), 7.18(m, 1H).

2. 5-bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-ylaminewas prepared following procedure 2 from1-(2-chloro-3,6-difluoro-phenyl)-ethanol and3,5-dibromo-pyrazin-2-ylamine.

Example II(d)

1. 1-(2-Chloro-3,6-difluoro-phenyl)-2-methyl-propan-1-ol was preparedfollowing the procedure of Example II(c) using isopropylmagnesiumchloride. ¹H NMR (400 MHz, DMSO-d₆) δ 0.63 (d, 3H), 1.06 (d, 3H), 2.19(m, 1H), 4.59 (m, 1H), 5.54 (d, 1H), 7.21 (m, 1H), 7.36 (m, 1H).

2.5-bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-2-methyl-propoxy]-pyrazin-2-ylaminewas prepared following procedure 2 from1-(2-chloro-3,6-difluoro-phenyl)-2-methyl-propan-1-ol and3,5-dibromo-pyrazin-2-ylamine.

Example II(e)

1. 2,6-Dichloro-3-fluoroacetophenone (15 g, 0.072 mol) was stirred inTHF (150 mL, 0.5 M) at 0° C. using an ice bath for 10 min. Lithiumaluminum hydride (from Aldrich, 2.75 g, 0.072 mol) was slowly added. Thereaction was stirred at ambient temperature for 3 h. The reaction wascooled in ice bath, and water (3 mL) was added drop wisely followed byadding 15% NaOH (3 mL) slowly. The mixture was stirred at ambienttemperature for 30 min. 15% NaOH (9 mL), MgSO₄ were added and themixture filtered to remove solids. The solids were washed with THF (50mL) and the filtrate was concentrated to give1-(2,6-Dichloro-3-fluoro-phenyl)-ethanol (14.8 gm, 95% yield) as ayellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 1.45 (d, 3H), 5.42 (m, 2H), 7.32(m, 1H), 7.42 (m, 1H).

2. 5-Bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylaminewas prepared following procedure 2 from1-(2,6-dichloro-3-fluoro-phenyl)-ethanol and3,5-dibromo-pyrazin-2-ylamine.

Example II(f)

5-Bromo-3-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-ylamine wasprepared following procedure 2 from(3-fluoro-2-trifluoromethyl-phenyl)-methanol and3,5-dibromo-pyrazin-2-ylamine.

Example I-1

A mixture of 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine(example I(a), 100 mg, 0.29 mmol),4-(4,4,5,5-tetramethyl-1,3-2-dioxabordan-2-yl) phenol (86 mg, 0.35mmol), bis(triphenylphosphine) palladium(II) chloride (8 mg, 0.009 mmol)and sodium carbonate (91 mg, 0.87 mmol) in ethylene glycol dimethylether (10 mL) and water (0.5 mL) was heated to reflux under nitrogen for18 hours. The reaction was cooled to ambient temperature and dilutedwith ethyl acetate. The mixture was washed with water, brine, dried overNa₂SO₄, and purified on silica column to afford4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenol as light pinecrystals (89 mg, 85% yield).

Example I-2

1. To a mixture of 4-(4,4,5,5-tetramethyl-1,3-2-dioxabordan-2-yl) phenol(5.00 g, 22.72 mmol) and Cs₂CO₃ (16.29 g, 49.98 mmol) in DMF (100 mL)were added 4(2-chloroethyl)morpholine hydrochloride (4.65 g, 24.99 mmol)and KI (0.2 g, 0.6 mmol). The mixture was stirred at 65° C. oil bath

for overnight and then cooled to ambient temperature. The reactionmixture was diluted with ethyl acetate (600 mL), and partitioned withwater. The water layer was extracted with ethyl acetate (2×50 mL). Thecombined ethyl acetate solution was washed with brine (5×100 mL), driedover Na₂SO₄, filtered, condensed, and dried in high vacuum to provide4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholine(6.8 g, 90% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.55 (d, 2H), 6.90 (d, 2H), 4.07 (t, 2H), 3.54 (m, 4H), 265 (t, 2H),2.43 (m, 4H).

2.3-(2,6-Dichloro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylaminewas prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine(example I(a)) and4{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholine(prepared in part 1) following procedure 3 as a white solid.

Example I-3

1.3-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholinewas prepared following the same procedure as4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholinein Example I-2 using 3-(4,4,5,5-tetramethyl-1,3-2-dioxabordan-2-yl)phenol in 92% yield as a white wax solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.28 (t, 1H), 7.22 (dt, 1H), 7.14 (d, 1H), 7.04 (ddd, 1H), 4.06 (t, 2H),3.56 (m, 4H), 2.49 (t, 2H), 2.45 (m, 4H).

2.3-(2,6-Dichloro-benzyloxy)-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylaminewas prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine(example I(a)) and3-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholineprepared in part 1 following procedure 3 as a light yellow solid.

Example I-4

1. To a mixture of 4-bromoindole (9.80 g, 50 mmol), pinacole diborate(13.97 g, 55 mmol), and KOAc (14.72 g, 150 mmol) in DMSO (200 mL) wasadded palladium catalyst PdCl₂(dppf)CH₂Cl₂ (1.22 g, 1.5 mmol). Thesystem was degassed, and then charged with nitrogen for three times. Themixture was stirred at 80° C. oil bath under nitrogen for 22 hours. TLCshowed the complete disappearance of the starting material4-bromoindole. The mixture was cooled to room temperature, and thenpoured to water (1 L). The product was extracted with ethyl acetate forthree times. The combined extracts were washed by brine for five timesto remove DMSO solvent, and then dried over Na₂SO₄. During the washingstep, the catalyst may precipitate out, which was removed by filtration.The ethyl acetate solution was filtered and condensed. The residue waspurified on a silica gel column eluting with EtOAc-hexane (9:1). Thefirst fraction provided the side product indole (1.25 g, 21% yield),R_(f)=0.55 (EtOAc-Hexane 5:1). The second fraction provided4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole as a whitesolid (8.01 g, 66%), R_(f) 0.46 (EtOAc-Hexane 5:1). ¹H NMR (300 MHz,DMSO-d₆): δ11.03 (bs, 1H, N—H)), 7.49 (d, J=7.7 Hz, 1H, H-5), 7.38 (dd,J=0.9 Hz, J=7.0 Hz, 1H. H-7), 7.38 (t, J=2.6 Hz, 1H, H-2), 7.06 (dd,J=7.7 Hz, J=7.0 Hz, 1H, H-6), 6.73 (bd, J=2.2 Hz; 1H, H-3), 1.32 (s,12H, 4CH₃); MS (m/e): 244 (M+H)⁺.

2. 3-(2,6-dichloro-benzyloxy)-5-(1H-indol-4-yl)-pyridin-2-ylamine wasprepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine(Example I(a)) and4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole followingprocedure 3. The first fraction was identified to be3-(2,6-dichloro-benzyloxy)-5-(1H-indol-4-yl)-pyridin-2-ylamine.

Example I-5

The same experiment was performed as Example 4, and the second fractionwas identified as3-[2-chloro-6-(1H-indol-4-yl)-benzyloxy]-5-(1H-indol-4-yl)-pyridin-2-ylamine.

Example I-6

2-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-pyrrole-1-carboxylicacid tert-butyl ester was prepared from5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (Example I(a)) andN-Boc pyrrole-2-boronic acid following procedure 3.

Example I-7

To a mixture of2-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-pyrrole-1-carboxylicacid tert-butyl ester (Example 6, 30 mg, 0.069 mmol) in ethanol/water(2:1, 10 mL) was added sodium carbonate (100 mg, 0.95 mmol). The mixturewas refluxed overnight. The reaction was cooled to ambient temperatureand extracted with ethyl acetate. The mixture was washed with water,brine, dried over Na₂SO₄, and purified on a silica gel column to afford3-(2,6-dichloro-benzyloxy)-5-(1H-pyrrol-2-yl)-pyridin-2-ylamine.

Examples I-8 to I-12

The compounds of Examples I-8 to I-12 were prepared according toprocedure 3 using 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamineand: 4-fluorophenyl boronic acid (Example I-8); phenyl boronic acid(Example I-9); 2-fluorophenyl boronic acid (Example I-10);3-fluorophenyl boronic acid (Example I-11); and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (ExampleI-12).

Example I-13

To a solution of5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (100 mg,0.28 mmol) in methylene chloride (5 mL) at 0° C., was addedmethanesulfonyl chloride (0.021 mL, 0.28 mmol) and 4-methylmorpholine(0.16 mL). The mixture was stirred at room temperature for 2 hr, anddiluted with ethyl acetate. The organic layers were washed with brine,dried over sodium sulfate and concentrated. The residue was purifiedwith a silica gel column eluting with hexane-ethyl acetate (5:1) to giveN-{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide.

Example I-14

To a solution of5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (100 mg,0.28 mmol) in acetonitrite (3 mL) at 0° C., was added pyridine (0.035mL, 1.5 eq.) and acetic anhydride (0.03 mL, 0.28 mmol). The mixture wasstirred at room temperature over night, and the precipitate was filteredto provideN-{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl) acetamideas a white solid.

Examples I-15 to I-35

The compounds of Examples I-15 to I-35 were prepared according toprocedure 3 from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamineand: 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (ExampleI-15); 4-methoxyphenyl boronic acid (Example I-16);3-aminobenzeneboronic acid (Example I-17);4-trifluoromethoxybenzeneboronic acid (Example I-18); 2-hydroxybenzeneboronic acid (Example I-19); 2-phenoxyphenylboronic acid (Example I-20);3,4-difluorophenylboronic acid (Example I-21);(3-isopropyl)phenylboronic acid (Example I-22);(2-trifluoromethylphenyl)boronic acid (Example I-23);(2-methoxyphenyl)boronic acid (Example I-24);(4-trifluoromethylphenyl)boronic acid (Example I-25);[(2-methylsulfonylamino)phenyl]boronic acid (Example I-26);4-hydroxymethylphenylboronic acid (Example I-27);3,4-methylenedioxyphenylboronic acid (Example I-28);2-trifluoromethoxyphenylboronic acid (Example I-29);4-methylthiophene-2-boronic acid (Example I-30);2-benzyloxyphenylboronic acid (Example I-31); 3-methoxyphenylboronicacid (Example I-32); 1-(tert-butoxycarbonyl)indole-2-boronic acid, andthe tert-butoxycarbonyl group was removed using 20% trifluoroacetic acidin dichloromethane (Example I-33); (3-fluoro-4-benzyloxyphenyl)boronicacid (Example I-34); and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (ExampleI-35).

Example I-36

To a solution of4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid (50 mg,0.13 mmol), HOBT (21 mg, 0.156 mmol), and EDC (30 mg, 0.156 mmol) in DMF(2 mL) was added N,N-diethylethylenediamine (0.022 mL, 0.156 mmol). Thereaction was stirred at room temperature for 24 hr, then diluted withEtOAc, and partitioned with H₂O. The organic was separated and theaqueous was extracted with EtOAc. The organic layers were combined,washed with saturated NaHCO₃, and concentrated to dryness under vacuum.The material was purified using column chromatography (silica gel, 99:1to 95:5 CH₂Cl₂/MeOH) to give4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-diethylamino-ethyl)-benzamide(45 mg, 72% yield) as a white solid.

Examples I-37 and I-38

The compounds of Examples I-37 and I-38 were prepared from4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid andN,N-diethyl-1,3-propanediamine (Example I-37) and1-methylpiperazine(Example I-38), following procedure 4.

Example I-39

1. A mixture of (+)-carbobenzyloxy-D-proline (1.5 g, 6 mmol), EDC (2.3g, 12 mmol), HOBt (800 mg, 6 mmol), TEA (1.5 mL) and pyrrolidine (853mg, 12 mmol) in DMF (20 mL) was stirred at rt for 18 hr. The reactionwas diluted with water and sodium bicarbonate, extracted withdichloromethane (3×). The combined DCM was concentrated and purified ona silica gel column to give(R)-2-(pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid benzylester. (R)-2-(pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acidbenzyl ester was hydrogenated using Pd/C in methanol at ambienttemperature for 20 hr to providepyrrolidin-1-yl-(R)-pyrrolidin-2-yl-methanone. To a solution ofpyrrolidin-1-yl-(R)-pyrrolidin-2-yl-methanone (1.2 g, 7.1 mmol) in THF(10 mL) at 0° C. was added B₂H₆ (10 mL, 10 mmol). The mixture was heatedto reflux for 16 hr. The reaction was acidified with HCl andconcentrated. The residue was basified to pH 10 with 2N NaOH andextracted with 5% methanol in DCM. The organic layer was concentratedand purified on a silica gel column to give 800 mg (73%) of(R)-2-pyrrolidin-1-ylmethyl-pyrrolidine.

2.{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanonewas prepared from4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid and(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Examples I-40 to I-45

The compounds of Examples I-40 to I-45 were prepared according toprocedure 4 from4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid and:(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-40);4-pyrrolidin-1-yl-piperidine (Example I-41); 4-piperidine ethanol(Example I-42); (3S)-(3-dimethylamino-pyrrolidine (Example I-43);(3R)-(3-dimethylamino-pyrrolidine (Example I-44); and(S)-3-cyclopropylaminomethyl-piperidine (prepared according to theprocedures for (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine in example I-39)(Example I-45).

Example I-46

1. To a solution of epichlorohydrin (from Aldrich, Milwaukee, 3.91 mL,50.0 mmol) in EtOH (100 mL) was added pyrrolidine (4.18 mL, 50.0 mmol)at room temperature. The mixture was stirred at 55˜60° C. for 20 hr,then refluxed for 3 hr. The solvent was removed under reduced pressureand crude 1-chloro-3-pyrrolidin-1-yl-propan-2-ol was obtained as an oil(10 g). This oily product was dissolved in 7 M ammonia in MeOH (40 mL)and stirred at room temperature overnight. Then another 30 mL of 7 Mammonia in MeOH was added and the mixture was stirred at 40° C.overnight. NMR showed that the starting material disappeared completely.The solvent was removed and the residue was dissolved in 2 N HCl andthen lyophilized to give 10.8 g of oil salt product, which was dissolvedin MeOH—H₂O at 0° C. and the resin (AG1-X8, hydroxide form) was added inportions with stirring until the pH of the solution is above 9.0. Afterfiltration, the filtrate was evaporated under reduced pressure to givethe free amine 1-amino-3-pyrrolidin-1-yl-propan-2-ol as yellowish oil(8.6 g). This crude product was used for the reaction without furtherpurification.

2.4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamidewas prepared from4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid and1-amino-3-pyrrolidin-1-yl-propan-2-ol following procedure 4.

Examples I-47 to I-52

The compounds of Examples I-47 to I-52 were prepared according toprocedure 4 from4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid and:3-fluoro-1-(2S)-pyrrolidin-2-ylmethyl-piperidine (prepared according tothe procedures for (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine) (ExampleI-47); 1-cyclopropyl-piperazine (Example I-48);(R)-2-[(cyclopropylmethyl-amino)-methyl]-pyrrolidine (prepared accordingto the procedures for (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine) (firstfraction, Example I-49; second fraction, Example I-50);N-(2-hydroxy-3-pyrrolidin-1-yl-propyl)-N-methyl amine (preparedaccording to the same procedure as 1-amino-3-pyrrolidin-1-yl-propan-2-ol(Example I-51); and(2S)-2-[(3R)-3-hydroxy-pyrrolidin-1-ylmethyl)-pyrrolidine (preparedaccording to the procedure for (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine)(Example I-52).

Example I-53

3-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid wasprepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine and3-(4,4,5,5-tetramethyl-(1,3,2]dioxaborolan-2-yl)-benzoic acid followingprocedure 3.

Example I-54

{3-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-Yl)phenyl)(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanonewas prepared from3-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid and(R)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Example I-55

1. To a solution of 4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenol(10.0 g, 45.5 mmol) and Cs₂CO₃ (23.5 g, 68.25 mmol) in DMF (60 mL) wasadded ethyl α-bromoacetate (11.6 g, 68.25 mmol). The mixture was stirredat room temperature for 24 hours, then diluted with-ethyl acetate,washed with water, dried over Na₂SO₄. After filtration and evaporation,the residue was dried under high vacuum to provide[4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenoxy]-acetic acid ethylester (12.52 g, 90% yield) as an oil.

2. A mixture of 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine(Example I(a)) (2.2 g, 6.3 mmol),[4-(4,4,5,5-tetramethyl-(1,3]dioxolan-2-yl)-phenoxy]-acetic acid ethylester (2.9 g, 1.5 eq.), bis(triphenylphosphine)palladium(II) chloride(136 mg) and sodium carbonate (1.93 g, 3.0 eq.) in ethylene glycoldimethyl ether (30 mL), DMF (5 mL) and water (8 mL) was heated to90–100° C. under nitrogen for 7 hr. The reaction was cooled to rt anddiluted with ethyl acetate. The mixture was washed with water, brine,dried and purified on silica column to afford(4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy)acetic acidethyl ester. This ester was treated with sodium carbonate and water atrt overnight. The reaction was diluted with ethyl acetate. The mixturewas washed with water, brine, dried and purified on silica column toafford4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy}-aceticacid.

Example I-56

2-(4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy)}-1-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanonewas prepared from4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy)acetic acidand (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Example I-57

2-{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy)-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanonewas prepared from4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy)acetic acidand (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Example I-58

3-(2,6-Dichloro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylamine wasprepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine andindole-5-boronic acid following procedure 3.

Example I-59

To a solution of3-(2,6-Dichloro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylamine (exampleI-58, 200 mg, 0.52 mmol) in acetic acid (4 mL) and trifluoroacetic-acid(1 mL) was added 1-methyl-4-piperidone (0.32 mL, 2.6 mmol). The solutionwas refluxing for over night, and evaporated. The residue was dissolvedin ethyl acetate, washed with saturated NaHCO₃ and brine, dried overNa₂SO₄, and condensed. The crude product was purified on a silica gelcolumn eluting with dichloromethane-methanol-triethyl amine (95:5:0.1)to provide3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine(103.5 mg, 41% yield) as an orange crystalline solid.

Example I-60

To a de-gassed solution of3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine(example I-61, 130 mg, 0.27 mmol) in methanol (50 mL) and acetic acid (5mL) was added 10% Pd/C (50 mg). The solution was degassed and chargedwith hydrogen for three times, and then was stirred under hydrogenballoon-for over night. The mixture was filtered through a celite pad,washed with methanol, and then condensed. The residue was dissolved inethyl acetate, washed with sat. NaHCO3 and brine, dried over Na₂SO₄, andcondensed. The crude product was purified on a silica gel column elutingwith dichloromethane-methanol-triethyl amine (95:5:0.1) to provide3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamineas a white solid.

Examples I-61–I-68

The compounds of Examples I-61 to I-68 were prepared according toprocedure 5 from3-(2,6-Dichloro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylamine and:morpholine (Example I-61); piperidine (Example I-62); pyrrolidine(Example I-63); diethylamine (Example I-64); pyrrolidin-3-yl-carbamicacid tert-butyl ester (Example I-65); 2,6-dimethyl-morpholine following(Example I-66); (R)-pyrrolidin-3-yl-acetamide (Example I-67); andpiperazin-1-yl-ethanone (Example I-68).

Example I-69

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylaminewas prepared from5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine andindole-5-boronic acid following procedure 3.

Examples I-70 to I-75

The compounds of Examples I-70 to I-75 were prepared according toprocedure 5 from3-(2-chloro-3,6-difluoro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylamineand: piperazin-1-yl-ethanone (Example I-70); 2,6-dimethyl-morpholine(Example I-71); (3S)-pyrrolidin-3-yl-acetamide (Example I-72);piperidine (Example I-73); morpholine (Example I-74); and pyrrolidine(Example I-75).

Example I-76

1. To a stirred solution of ethyl 5-bromo-1H-indole-2-carboxylate (5 g,18.6 mmol) in DMSO (75 mL, 0.25 M),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (11.2 g, 44.3mmol), potassium acetate (5.5 g, 56.0 mmol), and[bis(diphenylphosphino)ferrocene]dichloropalladium 11 (1.23 mmol) wereadded. The mixture was de-gassed and charged with nitrogen for threetimes, and then heated at 80° C. under nitrogen for overnight. Thereaction was cooled to ambient temperature and diluted with ethylacetate (2×100 mL). The mixture was washed with water (1×50 mL), brine(1×50 mL), dried over MgSO₄, and purified on a silica gel column toafford ethyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylateas an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.31 (t, 3H), 4.32(m, 2H), 7.18 (s, 1H), 7.42 (d, 1H), 7.54 (d, 1H), 8.05 (s, 1H), 11.96(s, 1H); MS IT/z 315 (M+1).

2.5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylicacid ethyl ester was prepared from5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine and5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylicacid ethyl ester following procedure 3.

Example I-77

To a mixture of ethyl5-{6-amino-5-[(2,6-dichlorobenzyl)oxy]pyridin-3-yl)11H-indole-2-carboxylate(2.5 g, 5.5 mmol) in methanol:water (60 mL 20 mL), lithium hydroxide(0.65 g, 27.1 mmol) was added. The reaction was heated to reflux forovernight. Most of the solvent was evaporated and the mixture wasacidified, and stirred for 10 min. The precipitate was filtered out andwashed with water to yield5-{6-amino-5-[(2,6-dichlorobenzyl)oxy]pyridin-3-yl)-1H-indole-2-carboxylicacid as tan solid.

Examples I-78 to I-85

The compounds of Examples I-78 to I-85 were prepared according toprocedure 4 from5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylicacid and: N-methylpiperazine (Example I-78);(3R)-3-dimethylamino-pyrrolidine (Example I-79);(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (prepared as in example I-39)(Example I-80); 2-pyrrolidin-1-yl-ethylamine (Example I-81);2-morpholin-4-yl-ethylamine (Example I-82); (S)-pyrrolidin-3-yl-carbamicacid tert-butyl ester (Example I-83), followed by de-protection of theBoc-group in 20% trifluoroacetic acid in dichloromethane (Example I-84);2-hydroxy-3-pyrrolidin-1-yl-propylamine (Example I-85).

Example I-86

4-(6-Amino-5-benzyloxy-pyridin-3-yl)-phenol was prepared from3-benzyloxy-5-bromo-pyridin-2-ylamine and4-(4,4,5,5-tetramethyl-1,3-2-dioxabordan-2-yl) phenol followingprocedure 3.

Example I-87

3-Benzyloxy-5-phenyl-pyridin-2-ylamine was prepared from3-benzyloxy-5-bromo-pyridin-2-ylamine and phenylboronic acid followingprocedure 3.

Example I-88

3-(3-Methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine was preparedaccording to procedure 6.

Examples I-89 to I-105

The compounds of Examples I-89 to I-105 were prepared according toprocedure 6 from: 2-chloro-4-fluoro-benzylbromide (Example I-89);2-chlorobenzylbromide (Example I-90); 2,5-dichlorobenzylbromide (ExampleI-91); 2-chloro-5-trifluoromethyl benzylbromide (Example I-92);2,4-Dichloro-5-fluoro-benzylbromide (Example I-93);2-chloro-3-trifluoromethyl-benzylbromide (Example I-94);2-chloro-3,6-difluoro-benzylbromide (Example I-95);3,4-dichloro-benzylbromide (Example I-96); 2-bromomethyl-benzonitrile(Example I-97); 2-chloro-6-fluoro-3-methyl-benzylbromide (Example I-98);2-bromomethyl-1,3,4-trifluoro-benzene (Example I-99);2-bromomethyl-1,3-difluoro-benzene (Example I-100);2-bromomethyl-1,3-difluoro-4-methyl-benzene (Example I-101);2-bromomethyl-4-chloro-1,3-difluoro-benzene (Example I-102);2-bromomethyl-1-chloro-3-fluoro-benzene (Example I-103);4-bromomethyl-2-fluoro-1-methoxy-benzene (Example I-104); and1-bromomethyl-3-nitro-benzene, followed by reduction of the nitro groupto amino and reaction with methanesulfonyl chloride (Example I-105).

Example I-106

5-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-3-(3-nitro-benzyloxy)-pyridin-2-ylaminewas synthesized according to procedure 7.

Examples I-107 to I-110

The compounds of Examples I-107 to I-110 were prepared according toprocedure 7 from: 1-bromomethyl-naphthalene (Example I-107);2-bromomethyl-3-chloro-1,4-difluoro-benzene (Example I-108);2-bromo-N-(4-isopropyl-phenyl)-2-phenyl-acetamide (Example I-109); and3-bromomethyl-5-chloro-benzo[b]thiophene (Example I-110).

Example I-111

{4-[6-Amino-5-(4-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl{-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanonewas synthesized according to procedure 8.

Examples I-112 to I-117

The compounds of Examples I-112 to I-117 were prepared according toprocedure 8 from: 2-bromomethyl-1-fluoro-3-trifluoromethyl-benzene(Example I-112); 2-bromomethyl-4-fluoro-1-trifluoromethyl-benzene(Example I-113); 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (ExampleI-114); 1-bromo-2-bromomethyl-benzene (Example I-115);1-bromomethyl-3-fluoro-2-trifluoromethyl-benzene (Example I-116); and2-bromomethyl-3-chloro-1,4-difluoro-benzene (Example I-117).

Examples I-118 to I-121

The compounds of Examples I-118 to I-121 were prepared according toprocedure 3 from 5-bromo-3-(2,6-difluoro-benzyloxy)-pyridin-2-ylamineand: 4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenol (Example I-118);4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholine(Example I-119); 4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-1H-indole(Example I-120); and 4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-benzoicacid (Example I-121).

Example I-122

{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanonewas prepared from4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid and(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Example I-123

{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanonewas prepared from4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid and(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Example I-124

{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-aceticacid ethyl ester was prepared from5-bromo-3-(2,6-difluoro-benzyloxy)-pyridin-2-ylamine and of[4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenoxy]-acetic acid ethylester following procedure 3.

Example I-125

{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-aceticacid ethyl ester (1.0 g, 2.41 mmol) was treated with sodium carbonate(1.28 g, 12.05 mmol) and water (10 mL) at 90–100° C. overnight. Thereaction was cooled to rt and diluted with ethyl acetate. The mixturewas washed with water, brine, dried and purified on silica column toafford4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy)acetic acid.

Example I-126

2-{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy)-1-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanonewas prepared from4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy)acetic acidand (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Example I-127

2-{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-1-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanonewas prepared from4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-acetic acidand (2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine following procedure 4.

Examples I-128 to I-134

The compounds of Examples I-128 to I-134 were prepared according toprocedure 3 from 4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenol and:5-bromo-3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine (ExampleI-128); 5-bromo-3-(2-chloro-4-fluoro-benzyloxy)-pyridin-2-ylamine(Example I-129); 5-bromo-3-(2,4-dichloro-benzyloxy)-pyridin-2-ylamine(Example I-130); 2-(2-amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile(Example I-131);5-bromo-3-(2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine (ExampleI-132); 5-bromo-3-(2-chloro-benzyloxy)-pyridin-2-ylamine (ExampleI-133); and 5-bromo-3-(4-tert-butyl-benzyloxy)-pyridin-2-ylamine(Example I-134).

Example I-135

1. To a solution of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (5.00 g,22.8 mmol) in methylene chloride (100 mL) and 4-methylmorpholine (16 mL)at 0° C. was added methanesulfonyl chloride (2.1 mL, 28 mmol). Themixture was stirred at room temperature for 2 hr, and diluted with ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate and concentrated to provideN-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamideas a white solid (6.32 g, 93% yield). MS m/z 298 (M+1).

2.N-{4-[6-Amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamidewas prepared following procedure 3 from2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile andN-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide.

Example I-136

10% NaOH solution (25 mL) was added toN-{4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-phenyl)methanesulfonamide(Example I-135, 650 mg, 1.65 mmol) in ethylene glycol (55 mL). Themixture was heated to reflux and allowed to stir for 24 hr. The reactionwas cooled to room temperature. Most of the solvent was evaporated andthe mixture was acidified. The precipitated solid was filtered out toafford2-[2-Amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-benzoicacid as light brown solid. The filtrate was neutralized and extractedwith EtOAc (5×20 mL). The organic layer was combined, dried over MgSO₄,and concentrated to yield2-[2-Amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-benzamideas an off-white solid.

Example I-137

2-[2-Amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-benzoicacid was prepared as in Example I-136.

Example I-138 to I-140

The compounds of Examples I-138 to I-140 were prepared according toprocedure 4 from2-[2-amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-benzoicacid and: N-methyl-piperazine (Example I-138); 2-hydroxyethylamine(Example I-139); and isobutylamine (Example I-140).

Example I-141

5-Bromo-3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine (Example I(e),9.00 g, 27.0 mmol), 4-carboxybenzeneboronic acid (4.41 g, 27.0 mmol),tetrakis(triphenylphosphine)palladium(0) (0.99 g, 0.9 mmol), potassiumcarbonate (13.1 g, 95.0 mmol), dimethylformamide (72 mL) and water (36mL) were charged to a 250 mL three neck round bottom flask equipped witha thermometer, a reflux condenser and magnetic stirring. The mixture waspurged with nitrogen and gradually heated from 81° C. to 98° C. over aperiod of 4 hr. Thin layer chromatography (ethyl acetate:hexane:aceticacid 4:6:0.5) showed a trace of starting material at Rf 0.7, product atRf 0.4 and many small impurities. The mixture was cooled to 45° C. Thesolids were collected by vacuum filtration, washed with 30 mL ofethanol:water 1:1 and discarded. The filtrate was diluted with 432 mL ofwater and 8 mL of 9 N potassium hydroxide solution (to pH 12–13), cooledin an ice bath and stirred for 30 minutes. The solids were collected byvacuum filtration and washed with 5 mL of water. The filtrate was cooledin an ice bath and acidified to pH 7.5 with acetic acid using a pHmeter. The solids were collected by vacuum filtration, washed with 10 mLof ethanol:water 1:1 and dried under vacuum to give 2.5 g of4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acidand a second compound as a brown solid in a ratio of about 1:1 by¹H-NMR. This material was discarded. The filtrate was acidified to pH6.5 with acetic acid using a pH meter. The solids were collected byvacuum filtration, washed with 10 mL of ethanol:water 1:1 and driedunder vacuum to give 3.6 g (36% yield) of4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid asa brown solid containing a 5–10% impurity by ¹H-NMR.

Examples I-142 to I-149

The compounds of Examples I-142 to I-149 were prepared according toprocedure 4 from4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acidand: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-142);(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-143);(3S)-3-dimethylamino-pyrrolidine (Example I-144);(S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed byde-protection of Boc-group with trifluoroacetic acid in dichloromethane(Example I-145); N-methylpiperazine (Example I-146);1-piperazin-1-yl-ethanone (Example I-147); 2-morpholin-4-yl-ethylamine(Example I-148); 3-morpholin-4-yl-propylamine (Example I-149).

Example I-150

5-Bromo-3-(2-chloro-benzyloxy)-pyridin-2-ylamine (4.50 g, 14.3 mmol),4-carboxybenzeneboronic acid (2.62 g, 15.8 mmol),tetrakis(triphenylphosphine)palladium(0) (0.56 g, 0.5 mmol), potassiumcarbonate (6.90 g, 50 mmol), dimethylformamide (36 mL), and water (18mL) were charged to a 250 mL three neck round bottom flask equipped witha thermometer, a reflux condenser and magnetic stirring. The mixture waspurged with nitrogen and gradually heated from 82 to 93° C. over aperiod of 4 hr. Thin layer chromatography (ethyl acetate:hexane:aceticacid 4:6:0.5) showed product at Rf 0.3 and a few small impurities. Themixture was cooled to 45° C. The solids were collected by vacuumfiltration, washed with 10 mL of ethanol:water 1:1 and discarded. Thecombined filtrate was diluted with 216 mL of water and 4 mL of 9 Npotassium hydroxide solution (to pH 12–13), cooled in an ice bath andstirred for 30 minutes with 3 g of Celite and 3 g of Norit. The solidswere collected by vacuum filtration through a pad of Celite and washedwith 10 mL of water. The solids were discarded. The combined filtratewas cooled in an ice bath and acidified to pH 7 with acetic acid using apH meter. The solids were collected by vacuum filtration, washed with 20mL of ethanol:water 1:1 and dried under vacuum to give 2.7 g (53% yield)of 4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-benzoic acid.

Examples I-151 to I-159

The compounds of Examples I-151 to I-159 were prepared according toprocedure 4 from 4-[6-amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-benzoicacid and: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-151);(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-152);(3S)-3-dimethylamino-pyrrolidine (Example I-153);pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed byde-protection of Boc-group with trifluoroacetic acid in dichloromethane(Example I-154); 4-pyrrolidin-1-yl-piperidine (Example I-155);N-methylpiperazine (Example I-156); 1-piperazin-1-yl-ethanone (ExampleI-157); 2-morpholin-4-yl-ethylamine (Example I-158); and3-morpholin-4-yl-propylamine (Example I-159).

Example I-160

2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile (9.0 g, 29.6mmol), 4-carboxybenzeneboronic acid (5.4 g, 32.5 mmol),tetrakis(triphenylphosphine)palladium(0) (1.1 g, 1.0 mmol), anhydrouspotassium carbonate (13.8 g, 70.0 mmol), dimethylformamide (72 mL) andwater (36 mL) were charged to a 250 mL three neck round bottom flaskequipped with a thermometer, a reflux condenser and magnetic stirring.The mixture was purged with nitrogen and gradually heated from 81 to 90°C. over a period of 2 hr. Thin layer chromatography (ethylacetate:hexane:acetic acid 4:6:0.5) showed a trace of starting materialat Rf 0.7, product at Rf 0.4 and an impurity at Rf 0.5. The mixture wascooled to 45° C. The sticky solids were collected by vacuum filtration,washed with 30 mL of ethanol:water 1:1 and discarded. The filtrate wasdiluted with 432 mL of water and 8 mL of 9 N potassium hydroxidesolution (to pH 12–13), cooled in an ice bath and stirred for 30minutes. The solids were collected by vacuum filtration and washed with20 mL of water. The solids were discarded. The filtrate was cooled in anice bath acidified with acetic acid to pH 7.5 using a pH meter. Thesolids were collected by vacuum filtration, washed with 20 mL water anddried under vacuum to give 8.5 g (83% yield) of4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-benzoic acid as a verydark solid.

Examples I-161 to I-170

The compounds of Examples I-161 to I-170 were prepared according toprocedure 4 from 4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-benzoicacid and: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-161);(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-162);(3S)-3-dimethylamino-pyrrolidine (Example I-163);(S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed byde-protection of Boc-group with trifluoroacetic acid in dichloromethane(Example I-164); 4-pyrrolidin-1-yl-piperidine (Example I-165);N-methylpiperazine (Example I-166); 1-piperazin-1-yl-ethanone (ExampleI-167); 1-methyl-piperidin-4-ylamine (Example I-168);2-Morpholin-4-yl-ethylamine (Example I-169); and3-morpholin-4-yl-propylamine (Example I-170).

Example I-171

5-Bromo-3-(2,4-dichloro-benzyloxy)-pyridin-2-ylamine (6.96 g, 20.0mmol), 4-carboxybenzeneboronic acid (3.98 g, 24.0 mmol),tetrakis(triphenylphosphine)-palladium(0) (0.74 g, 0.66 mmol), potassiumcarbonate (9.7 g, 70 mmol), dimethylformamide (35 mL)-and water (17 mL)were charged to a 250 mL three neck round bottom flask equipped with athermometer, a reflux condenser and magnetic stirring. The mixture waspurged with nitrogen and gradually heated from 81 to 95° C. over aperiod of 9 hr. Thin layer chromatography (ethyl acetate:hexane:aceticacid 4:6:0.5) showed a trace of starting material at Rf 0.7, product atRf 0.4 and impurities at Rf 0.5 and 0.3. The mixture was cooled to roomtemperature and allowed to stand over for about 48 hr. The solids werecollected by vacuum filtration, washed with 30 mL of ethanol:water 1:1and saved. The filtrate was diluted with 210 mL of water and 8 mL of 9 Npotassium hydroxide solution (to pH 12–13), cooled in an ice bath andstirred for 30 minutes. The solids were collected by vacuum filtrationand washed with 5 mL of water to give about 1 g of a mixture of productand a spot running with starting material. This mixture was discarded.The filtrate was cooled in an ice bath and acidified to pH 5–6 withabout 10 mL of acetic acid. The solids were collected by vacuumfiltration, washed with 10 mL of ethanol:water 1:1 and dried undervacuum to give 2.9 g (37% yield) of4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid as abrown solid.

Examples I-172 to I-181

The compounds of Examples I-172 to I-181 were prepared according toprocedure 4 from4-[6-amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid and:(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-172);(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-173);(3S)-3-dimethylamino-pyrrolidine (Example I-174);(S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed byde-protection of Boc-group with trifluoroacetic acid in dichloromethane(Example I-175); 4-pyrrolidin-1-yl-piperidine (Example I-176);N-methylpiperazine (Example I-177); 1-piperazin-1-yl-ethanone (ExampleI-178); 1-methyl-piperidin-4-ylamine (Example I-179);2-morpholin-4-yl-ethylamine (Example I-180); and3-morpholin-4-yl-propylamine (Example I-181).

Example I-182

5-Bromo-3-(2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine (5.80 g, 16.7mmol), 4-carboxybenzeneboronic acid (3.05 g, 18.4 mmol),tetrakis(triphenylphosphine)-palladium(0) (0.62 g, 0.6 mmol), potassiumcarbonate (8.10 g, 58 mmol), dimethylformamide (47 mL) and water (23 mL)were charged to a 250 mL three neck round bottom flask equipped with athermometer, a reflux condenser and magnetic stirring. The mixture waspurged with nitrogen and gradually heated from 81 to 93° C. over aperiod of 4 hr. Thin layer chromatography (ethyl acetate:hexane:aceticacid 4:6:0.5) showed product at Rf 0.6 and a few small impurities. Themixture was cooled to 45° C. The solids were collected by vacuumfiltration, washed with 10 mL of ethanol:water 1:1 and discarded. Thefiltrate was diluted with 300 mL of water and 4 mL of 9 N potassiumhydroxide solution (to pH 12–13), cooled in an ice bath and stirred for30 minutes with 3 g of Celite and 3 g of Norit. The solids werecollected by vacuum filtration through a pad of Celite and washed with10 mL of water. The solids were discarded. The filtrate was cooled in anice bath and acidified to pH 7.3 with acetic acid using a pH meter. Thesolids were collected by vacuum filtration, washed with 20 mL ofethanol:water 1:1 and dried under vacuum to give 4.5 g (69% yield) of4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzoic acid asa brown solid.

Examples I-183 to I-192

The compounds of Examples I-183 to I-192 were prepared according toprocedure 4 from4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzoic acidand: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-183);(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-184);(3S)-3-dimethylamino-pyrrolidine (Example I-185);pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed byde-protection of Boc-group with trifluoroacetic acid in dichloromethane(Example I-186); 4-pyrrolidin-1-yl-piperidine (Example I-187);N-methylpiperazine (Example I-188); 1-piperazin-1-yl-ethanone (ExampleI-189); 1-methyl-piperidin-4-ylamine (Example I-190);2-morpholin-4-yl-ethylamine (Example I-191); and3-morpholin-4-yl-propylamine (Example I-192).

Example I-193

2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile (9.0 g, 26.8mmol), 4-carboxybenzeneboronic acid (4.9 g, 30.0 mmol),tetrakis(triphenylphosphine)-palladium(0) (1.1 g, 1.0 mmol), anhydrouspotassium carbonate (13.1 g, 95 mmol), dimethylformamide (72 mL), andwater (36 mL) were charged to a 250 mL three neck round bottom flaskequipped with a thermometer, a reflux condenser and magnetic stirring.The mixture was purged with nitrogen and gradually heated from 81 to 96°C. over a period of 2 hr. Thin layer chromatography (ethylacetate:hexane:acetic acid 4:6:0.5) showed a trace of starting materialat Rf 0.8, product at Rf 0.5 and an impurity at Rf 0.4. The mixture wascooled to 45° C. and filtered to remove the solids. The filtrate wasdiluted with 432 mL of water and 8 mL of 9 N potassium hydroxidesolution (to pH 12–13), cooled in an ice bath and 4 g of Celite and 2 gof Norit were added. The solids were collected by vacuum filtrationthrough 4 g of Celite, washed with 30 mL of ethanol:water 1:1 anddiscarded The filtrate was cooled in an ice bath and acidified withacetic acid to pH 7.5 using a pH meter. The solids were collected byvacuum filtration, washed with 20 mL water and dried under vacuum togive 8.1 g (80% yield)4-[6-amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-benzoic acid as adark solid.

Examples I-194 to I-201

The compounds of Examples I-194 to I-201 were prepared according toprocedure 4 from4-[6-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-benzoic acid and:(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-194);(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-195);(3S)-3-dimethylamino-pyrrolidine (Example I-196); N-methylpiperazine(Example I-197); 1-piperazin-1-yl-ethanone (Example I-198);1-methyl-piperidin-4-ylamine (Example I-199);2-morpholin-4-yl-ethylamine (Example I-200); and3-morpholin-4-yl-propylamine (Example I-201).

Example I-202

5-Bromo-3-(2-chloro-4-fluoro-benzyloxy)-pyridin-2-ylamine (9.00 g, 27.0mmol), 4-carboxybenzeneboronic acid (4.41 g, 27.0 mmol),tetrakis(triphenylphosphine)-palladium(0) (0.99 g, 0.9 mmol), potassiumcarbonate (13.1 g, 95 mmol), dimethylformamide (72 mL), and water (36mL) were charged to a 250 mL three neck round bottom flask equipped witha thermometer, a reflux condenser and magnetic stirring. The mixture waspurged with nitrogen and gradually heated from 81 to 98° C. over aperiod of 4 hr. Thin layer chromatography (ethyl acetate:hexane:aceticacid 4:6:0.5) showed a trace of starting material at Rf 0.7, product atRf 0.4 and a few small impurities. The mixture was cooled to 45° C. Thesolids were collected by vacuum filtration, washed with 20 mL ofethanol:water 1:1 and discarded. The filtrate was diluted with 432 mL ofwater and 8 mL of 9 N potassium hydroxide solution (to pH 12–13), cooledin an ice bath and stirred for 30 minutes. The-solids were collected byvacuum filtration and washed with 5 mL of water to give about 1 g of amixture which was discarded. The filtrate was cooled in an ice bath andacidified to pH 6.5 with acetic acid using a pH meter. The solids werecollected by vacuum filtration, washed with 10 mL of ethanol:water 1:1and dried under vacuum to give 3.6 g (36% yield)4-[6-amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid asa brown solid.

Examples I-203 to I-210

The compounds of Examples I-203 to I-210 were prepared according toprocedure 4 from4-[6-Amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acidand: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-203);(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-204);(3S)-3-dimethylamino-pyrrolidine (Example I-205);(S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed byde-protection of Boc-group with trifluoroacetic acid in dichloromethane(Example I-206); N-methylpiperazine (Example I-207);1-piperazin-1-yl)-ethanone (Example I-208); 2-morpholin-4-yl-ethylamine(Example I-209); and 3-morpholin-4-yl-propylamine (Example I-210).

Example I-211

4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid methyl ester was prepared following procedure 3 from5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and4-methoxycarbonylbenzeneboronic acid as an off-white solid in 55% yield.¹H NMR (CDCl₃, 300 MHz) δ 3.94 (s, 3H), 4.79 (brs, 2H), 5.29–5.30 (d,2H, J, 1.6), 7.06–7.19 (dt, 1H, J, 4.1, 9.0), 7.2–7.26 (m, 1H),7.37–7.38 (d, 1H, 1.8), 7.58–7.61 (m, 2H), 8.01–8.02 (d, 2H, J, 1.8),8.08–8.11 (m, 2H).

To a stirred solution of4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid methyl ester (2.5 g, 6 mmol) in warm isopropanol (300 mL) was addedH₂O (100 mL) containing LiOH (0.74 g, 31 mol). The reaction immediatelyturned orange and was left to stir at room temperature for 18 hr. Thereaction was diluted with EtOAc (200 mL) and brine (50 mL). The organicwas separated off and the aqueous was extracted with EtOAc (2×50 mL).The organic layers were combined and washed with brine (2×25 mL), driedwith Na₂SO₄ and concentrated to dryness under vacuum to yield4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid (2.4 g, 6 mmol, 99%) as an off-white solid.

Examples I-212 to I-224

The compounds of Examples I-212 to I-224 were prepared according toprocedure 4 from4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid and: N-methylpiperazine (Example I-212);4-pyrrolidin-1-yl-piperidine (Example I-213); piperidin-4-yl-carbamicacid tert-butyl ester, followed by de-protection of Boc-group withtrifluoroacetic acid in dichloromethane (Example I-214);3,5-dimethyl-piperazine (Example I-215);(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-216);(3S)-3-dimethylamino-pyrrolidine (Example I-217);(R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed byde-protection of Boc-group with trifluoroacetic acid in dichloromethane(Example I-218); (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester,followed by de-protection of Boc-group with trifluoroacetic acid indichloromethane (Example I-219); 1-methyl-piperidin-4-ylamine (ExampleI-220); 2-pyrrolidin-1-yl-ethylamine (Example I-221);3-pyrrolidin-1-yl-propylamine (Example I-222);2-morpholin-4-yl-ethylamine (Example I-223); and3-morpholin-4-yl-propylamine (Example I-224).

Example I-225

3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid was prepared using the same procedure as4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid from from5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and3-methoxycarbonylbenzeneboronic acid.

Examples I-226 to I-239

The compounds of Examples I-226 to I-239 were prepared according toprocedure 4 from3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid and: N-methylpiperazine (Example I-226);4-pyrrolidin-1-yl-piperidine (Example I-227); piperidin-4-yl-carbamicacid tert-butyl ester, and then followed by de-protection of Boc-groupwith trifluoroacetic acid in dichloromethane (Example I-228);3,5-dimethyl-piperazine (Example I-229);(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-230);(3S)-3-dimethylamino-pyrrolidine (Example I-231);(R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed byde-protection of Boc-group with trifluoroacetic acid in dichloromethane(Example I-232); (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester,followed by de-protection of Boc-group with trifluoroacetic acid indichloromethane (Example I-233); 1-methyl-piperidin-4-ylamine (ExampleI-234); 2-pyrrolidin-1-yl-ethylamine (Example I-235);3-pyrrolidin-1-yl-propylamine (Example I-236);2-morpholin-4-yl-ethylamine (Example I-237);3-morpholin-4-yl-propylamine (Example I-238); and1-[4-(2-amino-ethyl)-piperazin-1-yl]-ethanone (Example I-239).

Example I-240

1. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5 g, 22.8mmol) was dissolved in DCM (100 mL, 0.2 M), triethylamine (15 mL, 5.0molar equivalent) was added to the mixture. The reaction was stirred at0° C. for 5 min. 3-chloropropane-1-sulfonyl chloride (4.2 g, 23.0 mmol)was added portion wise. The reaction was stirred at 0° C. for 1 hr andbrought gradually to room temperature, heated to reflux at 70° C. for 2hr. The mixture was cooled to room temperature, diluted with EtOAc andwater. The organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified through a silicacolumn to afford2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]isothiazolidine1,1-dioxide as off-white solid (5.2 g, 70% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 7.62 (d, 2H), 7.18 (d, 2H), 3.76 (t, 2H), 3.53 (t, 2H), 2.41(t, 2H), 1.28 (s, 12H).

2.3-(2-Chloro-3,6-difluoro-benzyloxy)-5-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylaminewas prepared following procedure 3 from5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]isothiazolidine1,1-dioxide.

Example I-241

3-(2,6-Dichloro-benzyloxy)-5-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylaminewas prepared following procedure 3 from5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine and2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]iso-thiazolidine1,1-dioxide.

Example I-242

5-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-3-(2-fluoro-6-trifluoromethyl-benzyloxy)-pyridin-2-ylaminewas prepared according to procedure 8.

Example I-243

2-Diethylamino-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl)amidewas synthesized according to procedure 9.

Examples I-244 to I-266

The compounds of Examples I-244 to I-266 were prepared followingprocedure 9.

Examples I-267 to I-269

The compounds of Examples I-267 to I-269 were prepared according toprocedure 3, with purification by reversed phase preparative HPLCeluting with acetonitrile-water-trifluoroacetic acid system and obtainedas trifluoroacetic acid salts, from5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and:2-(dimethylaminomethyl)-phenylboronic acid (Example I-267);3-(pyrrolidin-1-yl)-phenylboronic acid (Example I-268)and-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide(Example I-269).

Example I-270

5-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophene-2-carboxylicacid was prepared following procedure 3 starting from5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-2-ylamine and5-carboxythiophene-2-boronic acid.

Examples I-271 to I-276

Examples I-271 to I-276 were prepared according to procedure 4 from5-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophene-2-carboxylicacid and: N-methylpiperazine (Example I-271);(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-272);1-methyl-piperidin-4-yl)-amine (Example I-273); 3,5-dimethyl-piperazine(Example I-274); 2-pyrrolidin-1-yl-ethylamine (Example I-275); and4-pyrrolidin-1-yl-piperidine (Example I-276).

Example I-277

4-[6-Amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-y]-benzoicacid was prepared using the same procedure as4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid from5-bromo-3-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine and4-methoxycarbonylbenzeneboronic acid.

Examples I-278 to I-285

Examples I-278 to I-285 were prepared according to procedure 4 from4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzoicacid and: 4-pyrrolidin-1-yl-piperidine (Example I-278);1-methyl-piperidin-4-ylamine (Example I-279); 3,5-dimethyl-piperazine(Example I-280); 3-dimethylamino-pyrrolidine (Example I-281);(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-282);2-morpholin-4-yl-ethylamine (Example I-283); N-methylpiperazine (ExampleI-284); and 4-acetyl-piperazin-1-yl)-ethylamine (Example I-285).

Examples I-286 to I-289

The compounds of Examples I-286 to I-289 were prepared followingprocedure 9.

Example I-290

4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid was prepared using the same procedure as4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid from5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamineand 4-methoxycarbonylbenzeneboronic acid.

Examples I-291 to I-296

The compounds of Examples I-291 to I-296 were prepared according toprocedure 4 from4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}benzoicacid and: (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example I-291);1-methyl-piperidin-4-ylamine (Example I-292);(R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed byde-protection of Boc-group with trifluoroacetic acid in dichloromethane(Example I-293); 4-pyrrolidin-1-yl-piperidine (Example I-294);N-methyl-piperazine (Example I-295); and 3,5-dimethyl-piperazine(Example I-296).

Examples I-297 to I-299

The compounds of Examples I-297 to I-299 were prepared followingprocedure 9.

Examples I-300 to I-661 were prepared according to the proceduresreferenced in the Tables herein, except as specifically described in thefollowing paragraphs. When multiple procedures are referenced in theTables separated by “/”, the indicated procedures were performedsequentially.

Example I-311

3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}benzoicacid was prepared using the same procedure as4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid from5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamineand 3-methoxycarbonylbenzeneboronic acid.

Example I-312

3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanonewas prepared following procedure 4 starting from3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid and 1-methyl-piperidin-4-ylamine.

Example I-330

4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid was prepared using the same procedure as4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid from5-bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-2-ylamineand 4-methoxycarbonylbenzeneboronic acid.

Example I-331

4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamidewas prepared following procedure 4 starting from4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid and the corresponding amine.

Example I-342

3-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid was prepared using the same procedure as4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid from5-bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-2-ylamineand 3-methoxycarbonylbenzeneboronic acid.

Example I-343

(3-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanonewas prepared following procedure 4 starting from3-(6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl)-benzoicacid and the corresponding amine.

Example I-359

1. Preparation of 2-hydroxy-7-oxa-4-azonia-spiro[3.5]nonane: To asolution of morpholine (17.4 mL, 0.2 mol, 1.0 eq.) in ethanol (20 mL)was added epichlorohydrin (16.1 ml, 1.03 eq.) from the addition funnel.The reaction was cooled with an ice water bath and graduallyraised-to-room temperature. After 24 hr, the reaction was concentratedat 50° C. until no more distillate could be condensed. The resulting oilwas stored at room temperature for 24–48 hr or until a significant massof crystals was observed. The slurry was diluted with acetone andfiltered. The solids were dried under high vacuum. This provided 20 g ofcrystalline product. The mother liquors could be concentrated and thecrystallization process repeated in increase recovery.

2. Preparation of1-Morpholin-4-yl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-propan-2-ol:4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (440 mg, 2 mmol)was added to a stirred suspension of NaH (96 mg, 2 eq) in DMF (10 mL) at0° C. After 1 hr, 2-hydroxy-7-oxa-4-azonia-spiro[3.5]nonane (714 mg, 2eq.) was added. The mixture was stirred at room temperature overnight.The reaction mixture was poured into sat'd NH₄Cl solution, and extractedwith ethyl acetate. The extracts were washed with brine, dried overNa₂SO₄ and condensed to dryness. The crude product was purified with asilica gel column eluting with 2% methanol in methylene chloride toafford 220 mg of product as a pink solid (30%). ¹H NMR (400 MHz,DMSO-d₆): δ 7.58 (d, J=8.2 Hz, 2H), 6.915 (d, J=7.8 Hz, 2H), 4.89 (d,J=2.0 Hz, 1H), 3.98 (m, 3H), 3.55 (m, 4H), 2.40 (m, 6H), 1.27 (s, 12H).MS (m/e): 364 [M+H]+(100%).

3.1-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3yl}-phenoxy)-3-morpholin-4-yl-propan-2-olwas prepared following procedure 3 starting from5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamineand1-morpholin-4-yl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-propan-2-ol.

Example I-371

4-Methyl-piperazine-1-carboxylic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amidewas prepared according to procedure 10.

Example I-386

3-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acidwas prepared using the same procedure as4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid from 5-bromo-3-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-2-ylamineand 3-methoxycarbonylbenzeneboronic acid.

Example I-387

(3-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanonewas prepared following procedure 4 starting from3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acidand 3,5-dimethyl-piperazine.

Example 399

4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl)-benzoic acidwas prepared using the same procedure as4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid from 5-bromo-3-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridine-2-ylamineand 4-methoxycarbonylbenzeneboronic acid

Example 400

4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamidewas prepared following procedure 4 starting from4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acidand 2-pyrrolidin-1-yl-ethylamine.

Example I-454

To a solution of5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine(5.00 g, 13.15 mmol) in DMF (73 mL) and water (1 mL) was added Zn(CN)₂(4.50 g, 26.3 mmol), Pd₂(dba)₃ (0.602 g, 0.65 mmol), and DPPF (0.86 g,1.55 mmol). The mixture was degassed and charged with nitrogen for threetime, and then stirred under nitrogen at 100° C. for 3 hr. The reactionsolution was partitioned between ethyl acetate and water. The organiclayer was washed with a solution of sat. NH₄Cl-conc. NH₄OH-water(4:1:4), then dried over MgSO₄. The crude product was purified on asilica gel column eluting with ethyl acetate-hexanes (1:4) to provide6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-nicotinonitrile as awhite solide (4.15 g, 97% yield).

Example I-455

6-Amino-5-[1-(2,6-dichloro-3-cyano-phenyl)-ethoxy]-nicotinonitrile wasobtained as a side product from the preparation of6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-nicotinonitrile.

Example I-456

5-Aminomethyl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylaminewas prepared with the reduction of6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-nicotinonitrile. Toa solution of borane in THF (1.0 M, 16.8 mL, 16.8 mmol) was added6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]nicotinonitrile (785mg, 2.41 mmol) in anhydrous THF (8 mL) at 0° C. under nitrogen. Thereaction solution was stirred under nitrogen at 0° C. for 5 hr, and thenHCl solution (6 N, 12 mL) was added slowly followed with the addition ofwater (12 mL) and methanol (80 mL). The mixture was stirred forovernight. After evaporation of solvents, the residue was partitionedbetween dichloromethane and NaOH solution (1 N). The water layer wasextracted for three times, and the combined extracts were dried overMgSO₄. After filtration, evaporation and high vacuum dry, a white solidproduct was obtained (750 mg, 94% yield).

Example I-457

(R)-2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid(6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylmethyl)amidewas prepared with the same procedure as Step 4 in procedure 11.

Example I-462

(S)-1-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)ethane-1,2-diolwas prepared as follow: To a solution of asymmetic dihydroxylation-mix α(2.33 g) in a 1:1 mixture of t-BuOH and water (8 mL each) cooled to 0°C. was added3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-vinyl-pyridin-2-ylamine(500 mg, 1.67 mmol). The reaction mixture was stirred at 0° C. untilconsumption of the starting material. Three more loadings of AD-mix αwas added periodically to increase the reaction rate. Water was added (5mL) and the mixture was extracted with EtOAc (3×20 mL). The combinedorganic layer was dried over Na₂SO₄, and concentrated. The crude productwas purified by reverse phase HPLC to provide(S)-1-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-ethane-1,2-diol(320 mg, 53% yield).

Example I-463

(R)-1-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-ethane-1,2-diolwas prepared with the same procedure as Example I-462 with AD-mix α.

Examples II-1 to II-6

The compounds of Examples II-1 to II-6 were prepared according to theSuzuki coupling procedure 3 from5-bromo-3-(2,6-dichloro-benzyloxy)-pyrazin-2-ylamine and:4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (Example II-1);2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]isothiazolidine1,1-dioxide (Example II-2);3-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholine(Example II-3);4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholine(Example II-4);4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (ExampleII-5); and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid(Example II-6).

Example II-7

{4-[5-Amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-phenyl)[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanonewas prepared following the amidation procedure 4 from4-[5-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-benzoic acid and(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine.

Example II-8

{4-[5-Amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-ylphenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone was preparedfollowing the amidation procedure 4 from4-[5-amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-benzoic acid and4-pyrrolidin-1-yl-piperidine.

Examples II-9 to II-32

The compounds of Examples II-9 to II-32 were prepared following theSuzuki coupling procedure 3 from5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylamine and thefollowing compounds prepared according to the procedure in ExampleI-243: 2-morpholin-4-yl-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-9); 2-piperidin-1-yl-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-10); 2-(4-hydroxy-piperidin-1-yl)-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-11); 2-pyrrolidin-1-yl-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-12); 2-[(3R)-3-Hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-13); 2-[(2S)-2-Hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-14); 2-(cyclopropylmethyl-amino)-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-15); 2-dimethylamino-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-16); 2-diethylamino-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-17); 2-(4-acetyl-piperazin-1-yl)-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-18); 2-[4-(2-hydroxy-acetyl)-piperazin-1-yl]-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-19); 2-cyclopropylamino-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-20); 2-[(3R)-2-Hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-21); 2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-22); 2-(4-acetyl-piperazin-1-yl)-ethanesulfonic acid[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-23); 2-piperidin-1-yl-ethanesulfonic acid[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-24); 2-diethylamino-ethanesulfonic acid [3-(4,4, 5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (Example II-25);2-morpholin-4-yl-ethanesulfonic acid[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-26); 2-pyrrolidin-1-yl-ethanesulfonic acid[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-27); 2-dimethylamino-ethanesulfonic acid[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-28); 2-[4-(2-hydroxy-acetyl)-piperazin-1-yl]-ethanesulfonic acid[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-29); 2-(cyclopropylmethyl-amino)-ethanesulfonic acid[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-30); 2-[(3R)-3-hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-31); and 2-cyclopropylamino-ethanesulfonic acid[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (ExampleII-32).

Example II-33

4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzoicacid was prepared following the Suzuki coupling procedure 3 from5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylamine and4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-benzoic acid.

Example II-34

{4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanonewas prepared following the amidation procedure 4 from4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzoicacid and (2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine.

Examples II-35 to II-46

The compounds of Examples II-35 to II-46 were prepared according to theamidation procedure 4 from4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzoicacid and: 2-pyrrolidin-1-yl-ethylamine (Example II-35);(S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed byde-protection of Boc-group with trifluoroacetic acid in dichloromethane(Example II-36); 1-[4-(2-amino-ethyl)-piperazin-1-yl]-ethanone (ExampleII-37); 3-pyrrolidin-1-yl-propylamine (Example II-38);(3S)-3-dimethylamino-pyrrolidine (Example II-39);(R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed byde-protection of Boc-group with trifluoroacetic acid in dichloromethane(Example II-40); 3,5-dimethyl-piperazine (Example II-41);4-pyrrolidin-1-yl-piperidine (Example II-42);3-morpholin-4-yl-propylamine (Example II-43);1-methyl-piperidin-4-ylamine (Example II-44);2-morpholin-4-yl-ethylamine (Example II-45); and N-methylpiperazine(Example II-46).

Example II-47

3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzoicacid was prepared following the Suzuki coupling procedure 3 from5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylamine (ExampleII(b)) and 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid(Aldrich, Milwaukee).

Examples II-48 to II-60

The compounds of Examples II-48 to II-60 were prepared according to theamidation procedure 4 from3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzoicacid and: N-methylpiperazine (Example II-48);(R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followed byde-protection of Boc-group with trifluoroacetic acid in dichloromethane(Example II-49); (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester,followed by de-protection of Boc-group with trifluoroacetic acid indichloromethane (Example II-50); 3,5-dimethyl-piperazine (ExampleII-51); 3-morpholin-4-yl-propylamine (Example II-52);4-pyrrolidin-1-yl-piperidine (Example II-53);(3S)-3-dimethylamino-pyrrolidine (Example II-54);2-pyrrolidin-1-yl-ethyl amine (Example II-55);1-methyl-piperidin-4-ylamine (Example II-56);(2S)-pyrrolidin-1-ylmethyl-pyrrolidine (Example II-57);2-morpholin-4-yl-ethylamine (Example II-58);2-(4-Acetyl-piperazin-1-yl)-ethylamine (Example II-59); and3-pyrrolidin-1-yl-propylamine (Example II-60).

Example II-61

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(1H-indol-5-y)-pyrazin-2-ylaminewas prepared from5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylamine andindole-5-boronic acid following procedure 3.

Examples II-62 to II-68

The compounds of Examples II-62 to II-68 were prepared according toprocedure 5 from3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(1H-indol-5-yl)-pyrazin-2-ylamineand: pyrrolidine (Example II-62); diethylamine (Example II-63);1-piperazin-1-yl-ethanone (Example II-64); 2,6-dimethyl-morpholine(Example II-65); N—(S)-pyrrolidin-3-yl-acetamide (Example II-66);piperidine (Example II-67); and morpholine (Example II-68).

Example II-69

3-[1-(2-Chloro-3,6-difluoro-phenyl)-2-methyl-propoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylaminewas prepared following the Suzuki coupling procedure 3 from5-bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-2-methyl-propoxy]-pyrazin-2-ylamineand4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholine.

Example II-70

(3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine,compound with trifluoro-acetic acid, was prepared following the Suzukicoupling procedure 3 from5-bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-2-methyl-propoxy]-pyrazin-2-ylamineand4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholine.The product was purified with a reversed phase C-18 preparative HPLCeluting with acetonitrile-water-trifluoroacetic acid and obtained as atrifluoroacetic acid salt.

Examples II-71 to II-83

The compounds of Examples II-71 to II-83 were prepared according to theSuzuki coupling procedure 3 from5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamineand:4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholine,followed by purification with a reversed phase C-18 preparative HPLCeluting with acetonitrile-water-trifluoroacetic acid and obtained as atrifluoroacetic acid salt (Example II-71);N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methane-sulfonamide(Example II-72); 2-pyrrolidin-1-yl-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(prepared as in Example I-243) (Example II-73);2-(4-hydroxy-piperidin-1-yl)-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(prepared as in Example I-243) (Example II-74);2-piperidin-1-yl-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(prepared according to the procedure in Example I-243) (Example II-75);2-(cyclopropylmethyl-amino)-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(prepared as in Example I-243) (Example II-76);2-[(3R)-3-Hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(prepared as in Example I-243) (Example II-77);2-[(2S)-2-Hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(prepared as in Example I-243) (Example II-78);2-dimethylamino-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(prepared as in Example I-243) (Example II-79);2-morpholin-4-yl-ethanesulfonic acid(4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(prepared as in Example I-243) (Example II-80);2-diethylamino-ethanesulfonic acid[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(prepared as in Example I-243) (Example II-81);2-cyclopropylamino-ethanesulfonic acid(4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide(prepared as in Example I-243); and3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (ExampleII-83).

Examples II-84 to II-88

The compounds of Examples II-84 to II-88 were prepared according to theamidation procedure 4 from3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}benzoicacid and: (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester, followedby de-protection of Boc-group with trifluoroacetic acid indichloromethane (Example II-84); (R)-pyrrolidin-3-yl-carbamic acidtert-butyl ester, followed by de-protection of Boc-group withtrifluoroacetic acid in dichloromethane (Example II-85);(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine (Example II-86);2-(4-acetyl-piperazin-1-yl)-ethylamine (Example II-87); and(2S)-pyrrolidin-1-ylmethyl-pyrrolidine (Example II-88).

Example II-89

3-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid was prepared following the Suzuki coupling procedure 3 from5-bromo-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-ylamine and3-(4, 4, 5, 5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid.

Example II-90

3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamidewas prepared following the amidation procedure-4-from3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid and 1-methyl-piperidin-4-ylamine.

Example II-91

3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamidewas prepared following the amidation procedure 4 from3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid and 3-pyrrolidin-1-yl-propylamine.

Example II-92

(3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanonewas prepared following the amidation procedure 4 from3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid and 4-pyrrolidin-1-yl-piperidin-1-ylamine.

Example II-93

4-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzoicacid was prepared following the Suzuki coupling procedure 3 from5-bromo-3(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-ylamine and3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid.

Example II-94

4-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-N-(2-morpholin-4-yl-ethyl)-benzamidewas prepared following the amidation procedure 4 from4-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzoicacid and 2-morpholin-4-yl-ethylamine.

Example II-95

4-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-N-(1-methyl-piperidin-4-yl)-benzamidewas prepared following the amidation procedure 4 from4-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzoicacid and 1-methyl-piperidin-4-ylamine.

Examples II-96 to II-211 were prepared according to the proceduresreferenced in the Tables herein, except as specifically described in thefollowing paragraphs.

Example II-108

4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl)-benzoicacid was prepared using the same procedure as4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid from5-bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-ylamineand 4-methoxycarbonylbenzeneboronic acid.

Example II-109

4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamidewas prepared following procedure 4 starting from4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid and 3-pyrrolidin-1-yl-propylamine.

Example II-121

3-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzoicacid using the same procedures a4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid from5-bromo-3-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-ylamine and3-methoxycarbonylbenzeneboronic acid.

Example II-122

{3-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanonewas prepared following procedure 4 starting from3-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzoicacid and 4-pyrrolidin-1-yl-piperidin-1-ylamine.

Example II-145

4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy)-pyrazin-2-yl}-benzoicacid was prepared using the same procedure as4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid from5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamineand 4-methoxycarbonylbenzeneboronic acid.

Example II-148

4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((R)-2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamidewas prepared following procedure 4 starting from4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid and (R)-2-hydroxy-3-pyrrolidin-1-yl-propylamine.

Example II-156

4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoic acidwas prepared using the same procedure as4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid from 5-bromo-3-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-ylamineand 4-methoxycarbonylbenzeneboronic acid.

Example II-157

(4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanonewas prepared following procedure 4 starting from4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoic acidand 4-pyrrolidin-1-yl-piperidin-1-ylamine.

Example II-168

3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoic acidwas prepared using the same procedure as4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid from 5-bromo-3-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-ylamineand 3-methoxycarbonylbenzeneboronic acid.

Example II-169

3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy)-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamidewas prepared following procedure 4 starting from3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoic acidand 1-methyl-piperidin-4-ylamine.

Example II-193

5-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophene-2-carboxylicacid was prepared following procedure 3 starting from5-bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylamine and5-carboxythiophene-2-boronic acid.

Example II-194

{5-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophen-2-yl}-(4-methyl-piperazin-1-yl)-methanonewas prepared following procedure 4 starting from5-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophene-2-carboxylicacid and 4-methyl-piperazin-1-ylamine.

Examples L-1 to L-176 were prepared according to procedure 40. In Table5, the compounds are grouped into sections, with each section having aletter designation. Example numbers are assigned left to right by rows.For example, in Section A, the compounds in the top row, from left toright, are Examples L-1 to L-4, and the compounds in the second row are,from left to right, Examples L-5-L-8. % Inhibition is the percent c-METinhibition at 50 nM.

Examples L-177 to L-352 were prepared according to procedure 41. InTable 6, the compounds are grouped into sections, with each sectionhaving a letter designation. Example numbers are assigned left to rightby rows. % Inhibition is the percent c-MET inhibition at 1 μM.

Examples L-353 to L-548 were prepared according to procedure 42. InTable 7, the compounds are grouped into sections, with each sectionhaving a letter designation. Example numbers are assigned left to rightby rows. % Inhibition is the percent c-MET inhibition at 1 μM.

Examples L-549 to L-636 were prepared according to procedure 43. InTable 8, the compounds are grouped into sections, with each sectionhaving a letter designation. Example numbers are assigned left to rightby rows. % Inhibition is the percent c-MET inhibition at 1 μM.

BIOLOGICAL EXAMPLES

It will be appreciated that, in any given series of compounds, a rangeof biological activities will be observed. In its presently preferredaspects, this invention relates to novel compounds capable ofmodulating, regulating and/or inhibiting protein kinase activity. Thefollowing assays may be employed to select those compounds demonstratingthe optimal degree of the desired activity.

Assay Procedures

The following in vitro assay may be used to determine the level ofactivity and effect of the different compounds of the present inventionon one or more of the PKs. Similar assays can be designed along the samelines for any PK using techniques well known in the art. A literaturereference is provided (Technikova-Dobrova Z, Sardanelli A M, Papa S FEBSLett. 1991 Nov. 4; 292: 69–72).

The general procedure is as follows: compounds and kinase assay reagentsare introduced into test wells. The assay is initiated by addition ofthe kinase enzyme. Enzyme inhibitors reduce the measured activity of theenzyme.

In the continuous-coupled spectrophotometric assay the time-dependentproduction of ADP by the kinase is determined by analysis of the rate ofconsumption of NADH by measurement of the decrease in absorbance at 340nm. As the PK produces ADP it is re-converted to ATP by reaction withphosphoenol pyruvate and pyruvate kinase. Pyruvate is also produced inthis reaction. Pyruvate is subsequently converted to lactate by reactionwith lactate dehydrogenase, which simultaneously converts NADH to NAD.NADH has a measurable absorbance at 340 nm whereas NAD does not.

The presently preferred protocol for conducting the continuous-coupledspectrophotometric experiments for specific PKs is provided below.However, adaptation of this protocol for determining the activity ofcompounds against other RTKs, as well as for CTKs and STKs, is wellwithin the scope of knowledge of those skilled in the art.

HGFR Continuous-coupled Spectrophotometric Assay

This assay analyzes the tyrosine kinase activity of HGFR on the Met-2substrate peptide, a peptide derived from the activation loop of theHGFR.

Materials and Reagents:

-   -   1. HGF enzyme from Upstate (Met, active) Cat. #14-526    -   2. Met-2 Peptide (HGF Activation Loop) Ac-ARDMYDKEYYSVHNK        (MW=1960). Dissolve up in 200 mM HEPES, pH 7.5 at 10 mM stock.    -   3. 1 M PEP (phospho-enol-pyruvate) in 200 mM HEPES, pH 7.5.    -   4. 100 mM NADH (B-Nicotinamide Adenine Dinucleotide, Reduced        Form) in 200 mM HEPES, pH 7.5    -   5. 4 M MgCl₂ (Magnesium Chloride) in ddH₂O    -   6. 1 M DTT (Dithiothreitol) in 200 mM HEPES, pH 7.5    -   7. 15 Units/mL LDH (Lactic Dehydrogenase)    -   8. 15 Units/mL PK (Pyruvate Kinase)    -   9. 5 M NaCl dissolved in ddH₂O    -   10. Tween-20 (Protein Grade) 10% Solution    -   11. 1 M HEPES buffer:        (N-[2-Hydroxethyl]piperazine-N-[2-ethanesulfonic acid]) Sodium        Salt. Dissolve in ddH₂O, adjust pH to 7.5, bring volume to 1 L.        Filter at 0.1 μm.    -   12. HPLC Grade Water; Burdick and Jackson #365–4, 1×4 liters (or        equivalent)    -   13. 100% DMSO (SIGMA)    -   14. Costar #3880—black clear flat bottom half area plates for        K_(i) determination and % inhibition    -   15. Costar #3359—96 well polypropylene plates, round bottom for        serial dilutions    -   16. Costar #3635—UV-plate clear flat bottom plates for %        inhibition    -   17. Beckman DU-650 w/micro cell holders    -   18. Beckman 4-position micro cell cuvette        Procedure:

Prep Dilution Buffer (DB) for Enzyme (For 30 mL prep)

-   -   1. DB final concentration is 2 mM DTT, 25 mM NaCl₂, 5 mM MgCl₂,        0.01% Tween-20, and 50 mM HEPES buffer, pH 7.5.    -   2. Make up 50 mM HEPES by adding 1.5 mL 1 M HEPES into 28.1 mL        of ddH₂O. Add rest of the reagents. Into 50 mL conical vial, add        60 uL of 1 M DTT, 150 uL 5 M NaCl₂, 150 uL 1 M MgCl₂, and 30 uL        of 10% Tween-20 to give total volume of 30 mL.    -   3. Vortex for 5–10 seconds    -   4. Aliquot out DB at 1 mL/tube and label tubes as “DB HGFR”    -   5. Note: This can be prepared and stored ahead of time.    -   6. Freeze un-used aliquots in microcentrifuge tubes at −20° C.        freezer.

Prep Compounds

-   -   1. For compound dilution plate, add 4 uL of 10 mM stock into        column 1 of plate, and bring volume to 100 uL with 100% DMSO.    -   2. Set up the Precision 2000 dilution method. A final        concentration of 200 uM compound in 50% DMSO, 100 mM HEPES (1:2        serial dilution).

Prep Coupled Enzymatic Buffer:

-   -   1. Final concentration in assay:        -   Reagent (Stock Conc.) Final Conc. In Assay        -   a. PEP (1 M) 1 mM        -   b. NADH (100 mM) 300 uM        -   c. MgCl₂ (4 M) 20 mM        -   d. DTT(1 M) 2 mM        -   e. ATP (500 mM) 300 uM        -   f. HEPES 200 mM (pH 7.5) 100 mM        -   g. Pyruvate Kinase (PK) 15 units/mL        -   h. Lactic Dehydrogenase (LDH) 15 units/mL        -   i. Met-2 peptide (10 mM) 0.500 mM        -   j. HGFR 50 nM    -   2. For a 10 mL reaction buffer add 10 uL of 1 M PEP, 33 uL of        100 mM NADH, 50 uL of 4 M MgCl₂, 20 uL of 1 M DTT, 6 uL of 500        mM ATP, and 500 uL of 10 mM Met-2 peptide into 100 mM HEPES        buffer pH 7.5 and vortex/mix.    -   3. Add coupling enzymes, LDH and PK, into reaction mix. Mix by        gentle inversion.

Running Samples

-   -   1. Spectrophotometer settings:

i. Absorbance wavelength (λ): 340 nm ii. Incubation time:  10 min iii.Run time:  10 min iv. Temperature:  37° C.

-   -   2. Add 85 μL of CE reaction mix into each well of assay plate.    -   3. Add 5 μL of diluted compound into a well of the assay plate.    -   4. Add 5 μL of 50% DMSO for negative control into last column of        assay plate.    -   5. Mix with multi-channel pipettor or orbital shaker.    -   6. Pre-incubate for 10 minutes at 37° C.    -   7. Add 10 μL of 500 nM HGFR to each well of assay plate; the        final HGFR concentration is 50 nM in a total final volume of 100        μL.    -   8. Measure activity for 10 minutes at λ=340 nm and 37° C.

The following in vitro assays may be used to determine the level ofactivity and effect of the different compounds of the present inventionon one or more of the PKs. Similar assays can be designed along the samelines for any PK using techniques well known in the art.

Several of the assays described herein are performed in an ELISA(Enzyme-Linked Immunosorbent Sandwich Assay) format (Voller, et al.,1980, “Enzyme-Linked Immunosorbent Assay,” Manual of ClinicalImmunology, 2d ed., Rose and Friedman, Am. Soc. Of Microbiology,Washington, D.C., pp. 359–371). General procedure is as follows: acompound is introduced to cells expressing the test kinase, eithernaturally or recombinantly, for a selected period of time after which,if the test kinase is a receptor, a ligand known to activate thereceptor is added. The cells are lysed and the lysate is transferred tothe wells of an ELISA plate previously coated with a specific antibodyrecognizing the substrate of the enzymatic phosphorylation reaction.Non-substrate components of the cell lysate are washed away and theamount of phosphorylation on the substrate is detected with an antibodyspecifically recognizing phosphotyrosine compared with control cellsthat were not contacted with a test compound.

The presently preferred protocols for conducting the ELISA experimentsfor specific PKs is provided below. However, adaptation of theseprotocols for determining the activity of compounds against other RTKs,as well as for CTKs and STKs, is well within the scope of knowledge ofthose skilled in the art.

Other assays described herein measure the amount of DNA made in responseto activation of a test kinase, which is a general measure of aproliferative response. General procedure for this assay is as follows:a compound is introduced to cells expressing the test kinase, eithernaturally or recombinantly, for a selected period of time after which,if the test kinase is a receptor, a ligand known to activate thereceptor is added. After incubation at least overnight, a DNA labelingreagent such as 5-bromodeoxyuridine (BrdU) or H³-thymidine is added. Theamount of labeled DNA is detected with either an anti-BrdU antibody orby measuring radioactivity and is compared to control cells notcontacted with a test compound.

MET Transphosphorylation Assay

This assay is used to measure phosphotyrosine levels on a poly(glutamicacid:tyrosine, 4:1) substrate as a means for identifyingagonists/antagonists of met transphosphorylation of the substrate.

Materials and Reagents:

1. Coming 96-well ELISA plates, Coming Catalog #25805-96.

2. Poly(glu-tyr), 4:1, Sigma, Cat. No; P 0275.

3. PBS, Gibco Catalog #450-1300EB

4. 50 mM HEPES

5. Blocking Buffer: Dissolve 25 g Bovine Serum Albumin, Sigma Cat. NoA-7888, in 500 mL PBS, filter through a 4 μm filter.

6. Purified GST fusion protein containing the Met kinase domain, SUGEN,Inc.

7. TBST Buffer.

8. 10% aqueous (MilliQue H₂O) DMSO.

9. 10 mM aqueous (dH₂O) Adenosine-5′-triphosphate, Sigma Cat. No.A-5394.

10. 2× Kinase Dilution Buffer: for 100 mL, mix 10 mL 1 M HEPESat pH 7.5with 0.4 mL 5% BSA/PBS, 0.2 mL 0.1 M sodium orthovanadate and 1 mL 5 Msodium chloride in 88.4 mL dH₂O.

11. 4× ATP Reaction Mixture: for 10 mL, mix 0.4 mL 1 M manganesechloride and 0.02 mL 0.1 M ATP in 9.56 mL dH₂O.

12. 4× Negative Controls Mixture: for 10 mL, mix 0.4 mL 1 M manganesechloride in 9.6 mL dH₂O.

13. NUNC 96-well V bottom polypropylene plates, Applied ScientificCatalog # S-72092

14. 500 mM EDTA.

15. Antibody Dilution Buffer: for 100 mL, mix 10 mL 5% BSA/PBS, 0.5 mL5% Carnation® Instant Milk in PBS and 0.1 mL 0.1 M sodium orthovanadatein 88.4 mL TBST.

16. Rabbit polyclonal antophosphotyrosine antibody, SUGEN, Inc.

17. Goat anti-rabbit horseradish peroxidase conjugated antibody,Biosource, Inc.

18. ABTS Solution: for 1 L, mix 19.21 g citric acid, 35.49 g Na₂HPO₄ and500 mg ABTS with sufficient dH₂O to make 1 L.

19. ABTS/H₂O₂: mix 15 mL ABST solution with 2μL H₂O₂ five minutes beforeuse.

20. 0.2 M HCl

Procedure:

1. Coat ELISA plates with 2 μg Poly(Glu-Tyr) in 100 μL PBS,hold-overnight at 4° C.

2. Block plate with 150 μL of 5% BSA/PBS for 60 min.

3. Wash plate twice with PBS then once with 50 mM Hepes buffer pH 7.4.

4. Add 50 μl of the diluted kinase to all wells. (Purified kinase isdiluted with Kinase Dilution Buffer. Final concentration should be 10ng/well.)

5. Add 25 μL of the test compound (in 4% DMSO) or DMSO alone (4% indH₂O) for controls to plate.

6. Incubate the kinase/compound mixture for 15 minutes.

7. Add 25 μL of 40 mM MnCl₂ to the negative control wells.

8. Add 25 μL ATP/MnCl₂ mixture to the all other wells (except thenegative controls). Incubate for 5 min.

9. Add 25 μL 500 mM EDTA to stop reaction.

10. Wash plate 3× with TBST.

11. Add 100 μL rabbit polyclonal anti-Ptyr diluted 1:10,000 in AntibodyDilution Buffer to each well. Incubate, with shaking, at roomtemperature for one hour.

12. Wash plate 3× with TBST.

13. Dilute Biosource HRP conjugated anti-rabbit antibody 1:6,000 inAntibody Dilution buffer. Add 100 μL per well and incubate at roomtemperature, with shaking, for one hour.

14. Wash plate 1× with PBS.

15. Add 100 μl of ABTS/H₂O₂ solution to each well.

16. If necessary, stop the development reaction with the addition of 100μl of 0.2 M HCl per well.

17. Read plate on Dynatech MR7000 ELISA reader with the test filter at410 nM and the reference filter at 630 nM.

BrdU Incorporation Assays

The following assays use cells engineered to express a selected receptorand then evaluate the effect of a compound of interest on the activityof ligand-induced DNA synthesis by determining BrdU incorporation intothe DNA.

The following materials, reagents and procedure are general to each ofthe following BrdU incorporation assays. Variances in specific assaysare noted.

General Materials and Reagents:

1. The appropriate ligand.

2. The appropriate engineered cells.

3. BrdU Labeling Reagent: 10 mM, in PBS, pH7.4 (Roche MolecularBiochemicals, Indianapolis, Ind.).

4. FixDenat: fixation solution (Roche Molecular Biochemicals,Indianapolis, Ind.).

5. Anti-BrdU-POD: mouse monoclonal antibody conjugated with peroxidase(Chemicon, Temecula, Calif.).

6. TMB Substrate Solution: tetramethylbenzidine (TMB, ready to use,Roche Molecular Biochemicals, Indianapolis, Ind.).

7. PBS Washing Solution: 1×PBS, pH 7.4.

8. Albumin, Bovine (BSA), fraction V powder (Sigma Chemical Co., USA).

General Procedure:

1. Cells are seeded at 8000 cells/well in 10% CS, 2 mM Gin in DMEM, in a96 well plate. Cells are incubated overnight at 37° C. in 5% CO₂.

2. After 24 hours, the cells are washed with PBS, and then areserum-starved in serum free medium (0% CS DMEM with 0.1% BSA) for 24hours.

3. On day 3, the appropriate ligand and the test compound are added tothe cells simultaneously. The negative control wells receive serum freeDMEM with 0.1% BSA only; the positive control cells receive the ligandbut no test compound. Test compounds are prepared in serum free DMEMwith ligand in a 96 well plate, and serially diluted for 7 testconcentrations.

4. After 18 hours of ligand activation, diluted BrdU labeling reagent(1:100 in DMEM, 0.1% BSA) is added and the cells are incubated with BrdU(final concentration is 10 μM) for 1.5 hours.

5. After incubation with labeling reagent, the medium is removed bydecanting and tapping the inverted plate on a paper towel. FixDenatsolution is added (50 μl/well) arid the plates are incubated at roomtemperature for 45 minutes on a plate shaker.

6. The FixDenat solution is removed by decanting and tapping theinverted plate on a paper towel. Milk is added (5% dehydrated milk inPBS, 200 μl/well) as a blocking solution and the plate is incubated for30 minutes at room temperature on a plate shaker.

7. The blocking solution is removed by decanting and the wells arewashed once with PBS. Anti-BrdU-POD solution is added (1:200 dilution inPBS, 1% BSA, 50 μl/well) and the plate is incubated for 90 minutes atroom temperature on a plate shaker.

8. The antibody conjugate is removed by decanting and rinsing the wells5 times with PBS, and the plate is dried by inverting and tapping on apaper towel.

9. TMB substrate solution is added (100 μl/well) and incubated for 20minutes at room temperature on a plate shaker until color development issufficient for photometric detection.

10. The absorbance of the samples are measured at 410 nm (in “dualwavelength” mode with a filter reading at 490 nm, as a referencewavelength) on a Dynatech ELISA plate reader.

HGF-Induced BrdU Incorporation Assay

Materials and Reagents:

1. Recombinant human HGF (Cat. No. 249-HG, R&D Systems, Inc. USA).

2. BxPC-3 cells (ATCC CRL-1687).

Remaining Materials and Reagents, as above.

Procedure:

1. Cells are seeded at 9000 cells/well in RPMI 10% FBS in a 96 wellplate. Cells are incubated overnight at 37° C. in 5% CO₂.

2. After 24 hours, the cells are washed with PBS, and then are serumstarved in 100 μL serum-free medium (RPMI with 0.1% BSA) for 24 hours.

3. On day 3, 25 μL containing ligand (prepared at 1 μg/mL in RPMI with0.1% BSA; final HGF conc. is 200 ng/mL) and test compounds are added tothe cells. The negative control wells receive 25 μL serum-free RPMI with0.1% BSA only; the positive control cells receive the ligand (HGF) butno test compound. Test compounds are prepared at 5 times their finalconcentration in serum-free RPMI with ligand in a 96 well plate, andserially diluted to give 7 test concentrations. Typically, the highestfinal concentration of test compound is 100 μM, and 1:3 dilutions areused (i.e. final test compound concentration range is 0.137–100 μM).

4. After 18 hours of ligand activation, 12.5 μL of diluted BrdU labelingreagent (1:100 in RPMI, 0.1% BSA) is added to each well and the cellsare incubated with BrdU (final concentration is 10 μM) for 1 hour.

5. Same as General Procedure.

6. Same as General Procedure.

7. The blocking solution is removed by decanting and the wells arewashed once with PBS. Anti-BrdU-POD solution (1:100 dilution in PBS, 1%BSA) is added (100 μL/well) and the plate is incubated for 90 minutes atroom temperature on a plate shaker.

8. Same as General Procedure.

9. Same as General Procedure.

10. Same as General Procedure.

In Vivo Animal Models

Xenograft Animal Models

The ability of human tumors to grow as xenografts in athymic mice (e.g.Balb/c, nu/nu) provides a useful in vivo model for studying thebiological response to therapies for human tumors. Since the firstsuccessful xenotransplantation of human tumors into athymic mice,(Rygaard and Povisen, 1969, Acta Pathol. Microbial. Scand. 77:758–760),many different human tumor cell lines (e.g., mammary, lung,genitourinary, gastro-intestinal, head and neck, glioblastoma, bone, andmalignant melanomas) have been transplanted and successfully grown innude mice. The following assays may be used to determine the level ofactivity, specificity and effect of the different compounds of thepresent invention. Three general types of assays are useful forevaluating compounds: cellular/catalytic, cellular/biological and invivo. The object of the cellular/catalytic assays is to determine theeffect of a compound on the ability of a TK to phosphorylate tyrosineson a known substrate in a cell. The object of the cellular/biologicalassays is to determine the effect of a compound on the biologicalresponse stimulated by a TK in a cell. The object of the in vivo assaysis to determine the effect of a compound in an animal model of aparticular disorder such as cancer.

Suitable cell lines for subcutaneous xenograft experiments include C6cells (glioma, ATCC # CCL 107), A375 cells (melanoma, ATCC # C.RL 1619),A431 cells (epidermoid carcinoma, ATCC # C.RL 1555), Calu 6 cells (lung,ATCC # HTB 56), PC3 cells (prostate, ATCC # C.RL 1435), SKOV3TP5 cells,S114 (NIH3T3 fibroblast cell line genetically engineered for cMet andHGF expressions from NCl), U-87 MG (human malignant glioma, ATCC HTB 14)and NIH 3T3 fibroblasts genetically engineered to overexpress EGFR,PDGFR, IGF-1R or any other test kinase. The following protocol can beused to perform xenograft experiments:

Female athymic mice (BALB/c, nu/nu) are obtained from SimonsenLaboratories (Gilroy, Calif.). All animals are maintained underclean-room conditions in Micro-isolator cages with Alpha-dri bedding.They receive sterile rodent chow and water ad libitum.

Cell lines are grown in appropriate medium (for example, MEM, DMEM,Ham's F10, or Ham's F12 plus 5%–10% fetal bovine serum (FBS) and 2 mMglutamine (GLN)). All cell culture media, glutamine, and fetal bovineserum are purchased from Gibco Life Technologies (Grand Island, N.Y.)unless otherwise specified. All cells are grown in a humid atmosphere of90–95% air and 5–10% CO₂ at 37° C. All cell lines are routinelysubcultured twice a week and are negative for mycoplasma as determinedby the Mycotect method (Gibco).

Cells are harvested at or near confluency with 0.05% Trypsin-EDTA andpelleted at 450×g for 10 min. Pellets are resuspended in sterile PBS ormedia (without FBS) to a particular concentration and the cells areimplanted into the hindflank of the mice (8–10 mice per group, 2–10×10⁶cells/animal). Tumor growth is measured over 3 to 6 weeks using veniercalipers. Tumor volumes are calculated as a product oflength×width×height unless otherwise indicated. P values are calculatedusing the Students t-test. Test compounds in 50–100 μL excipient (DMSO,or VPD:D5W) can be delivered by IP injection at different concentrationsgenerally starting at day one after implantation.

Met Phosohorylation—Cellular Assay

Materials and Reagents:

1. Falcon 10 cm culture dishes.

2. A549 lung carcinoma cells.

3. F12K growth medium (with 2% FBS+2 mM glutamine.

4. F12K assay medium (with 0.1% BSA).

5. Fisher cell scrapers.

6. Lysis buffer (HNTG, 1 mM sodium orthovanidate, 1 mM PMSF and 2 mMsodium fluoride).

7. 1.5 mL Eppendorf tubes.

8. Eppendorf microcentrifuge.

9. BCA assay reagents A and B (#23223 and 23224, Pierce).

10. Sample tube rotator.

11. Gel blot container rotator.

12. 5× sample buffer.

13. Novex pre-cast tris-glycine 8% acrylamide gels.

14. Bio-Rad electrophoresis chamber.

15. SDS-PAGE buffer.

16. TBS (pH 7.6)+0.1% Triton X-100 (TBST), with and without 5% milk.

17. Western blot transfer buffer.

18. Osmonics nitrocellulose paper.

19. Bio-Rad Transblot paper.

20. Gel transfer apparatus.

21. Anti-phosphotyrosine (mouse monoclonal).

22. Bio-Rad Kaleidoscope Prestained Standards (161–0324).

23. Anti-h-met (C-28) rabbit polyclonal, conjugated and non-conjugatedwith agarose (#sc-161 AC and sc-161, Santa Cruz Biotechnology, Inc.).

24. Donkey and anti-rabbit Ig-HRP (NA 934, Amersham).

25. Sheet anti-mouselg-HRP (NA 931, Amersham).

26. SuperSignal West Pico Chemiluminescent Substrate (#34080, Pierce).

27. Saran Wrap.

28. Kodak BioMax exposure cassette.

29. Fuji X-ray film.

30. Kodak film developer.

Procedure:

1. Plate cells in 10 cm dishes with growth medium with 2% FBS+2 mMglutamine. Grow to near confluency.

2. Serum starve cells overnight in assay medium with 0.1% BSA.

3. Add drug to the plates, one dose per plate, usually in a 2-flodtitration. Add assay medium (with the same DMSO concentration as thedrugs) for no drug.

4. Incubate plates 4–5 hours with the drug, then add HG, 50 ng/mL for 10minutes.

5. Wash plates once with PBS, add 400 μl lysis buffer, and scrape offthe cells. Collect in 1.5 mL Eppendorf tubes.

6. After about 10–20 minutes in the lysis buffer, centrifuge lysates ina microcentrifuger at full speed (14,000 g) and collect the supernatantsin a separate Eppendorf tube.

7. Determine protein concentration with the BCA assay reagents.

8. Adjust sample concentration to 0.5 mg protein in 0.4 mL using lysisbuffer.

9. Add 15 μl anti-h-met AC for immunoprecipitation, rotate samples for 2hours at 4° C.

10. Wash samples 3 times with lysis buffer and resuspend in 35 μl 5×sample buffer.

11. Boil sample at 100° C. for 10 minutes and microcentrifuge at highestsetting for 30 minutes to pellet the agarose beads.

12. Load 15 μl each to 2 gels, one for anti-phosphorylation and theother for anti-h-met. Also load 10 μl of prestained standards, one laneper gel.

13. Run gel around 100–125 V, then transfer gel to nitrocellulose eitherovernight at 70 mAmps or 1 hour at 500 mAmps.

14. Block membranes on rotator for 1 hour in TBS+0.1% Triton X-100(TBST)+5% PBS. All steps from this point are at room temperature unlessotherwise unless otherwise noted.

15. Add 0.8 μg/mL antiphosphotyrosine and 0.25 μg/mL anti-h-met onrotator either for 2 hours or overnight.

16. Wash membranes 3 times 5 minutes each in TBST on rotator.

17. Add HRP-conjugated antibodies sheep anti-mouse for theantiphosphotyroeins; donkey anti-rabbit for the nati-h-met) at 1:5000for approximately 45 minutes on rotator.

18. Wash membranes 3 times for 5 minutes each in TBST on rotator.

19. Add the 2 reagents in the SuperSignal kit together in equal-volumes(3 mL+3 mL for each blot), rotate for 1–2 minutes.

20. Wrap blots in Saran Wrap and tape securely inside the exposurecassette.

21. In the darkroom with only the safety light on, place a sheet of filminside the cassette. After an allotted time, remove film and place inthe developer machine for automatic processing. Experiment with theexposure time to get proper exposure.

TABLES

TABLE 1 Met IC₅₀ MS m/z No. Structure Name (μM) ¹H-NMR (M + 1) I(a)

5-Bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine 5.3 (400 MHz,DMSO-d₆) δ 7.62(m, 1H), 7.56(m, 2H), 7.46(m,2H), 5.80(s, 2H), 5.22(s,2H) 349 I(b)

3-Benzyloxy-5-bromo-pyridin-2-ylamine >20 (400 MHz, DMSO-d₆) δ7.56(d,J=2 Hz, 1H), 7.47(d, J=7.2 Hz, 2H),7.38(m, 2H), 7.32(d, J=7.2 Hz,1H),7.26(d, J=2 Hz, 1H), 5.95(s, 2H),5.14(s, 2H) 280 I(c)

5-Bromo-3-(2,6-difluoro-benzyloxy)-pyridin-2-ylamine 40% at20 μM (400MHz, DMSO-d₆) δ 7.60(d, 1H),7.52(m, 1H), 7.40(d, 1H), 7.18(m,2H),5.81(br. S. 2H), 5.12(s, 2H) 315 (M+) I(d)

5-Bromo-3-(2-bromo-benzyloxy)-pyridin-2-ylamine >20 (400 MHz, DMSO-d₆) δ7.65(m, 2H), 7.60(d, 1H), 7.42(m,2H), 7.30(d, 1H), 5.94(s 2H), 5.13(s,2H) 357(M+) I(e)

5-Bromo-3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine >20 (400 MHz,DMSO-d₆) δ 7.80–7.30(m, 5H), 5.80(br s, 2H),5.15(s, 2H) 331 I(f)

5-Bromo-3-(2-chloro-4-fluoro-benzyloxy)-pyridin-2-ylamine (400 MHz,DMSO-d₆) δ 7.80–7.20(m, 5H), 5.95(br s, 2H),5.10(s, 2H) 331 I(g)

5-Bromo-3-(2,4-dichloro-benzyloxy)-pyridin-2-ylamine (400 MHz, DMSO-d₆)δ 7.80–7.50(m, 5H), 6.20(br s, 2H),5.20(s, 2H) 348 I(h)

2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile (400 MHz,DMSO-d₆) δ 7.90–7.30(m, 6H), 5.90(br s, 2H),5.20(s, 2H) 304 (M+) I(i)

5-Bromo-3-(2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine (400 MHz,DMSO-d₆) δ 7.80–7.30(m, 6H), 6.00(br s, 2H),5.25(s, 2H) 347 I(j)

5-Bromo-3-(4-tert-butyl-benzyloxy)-pyridin-2-ylamine (400 MHz, DMSO-d₆)δ 7.50–7.20(m, 6H), 5.85(br s, 2H),5.05(s, 2H), 1.25(s, 9H) 335 (M+)I(k)

5-Bromo-3-(2-chloro-benzyloxy)-pyridin-2-ylamine (400 MHz, DMSO-d₆) δ7.70–7.20(m, 6H), 5.90(br s, 2H),5.15(s, 2H) 313 I(l)

5-Bromo-3-(2-chloro-3.6-difluoro-benzyloxy)-pyridin-2-ylamine 5.3(CDCl₃, 300 MHz) δ 4.7–4.8(brs, 2H), 5.21(s, 2H), 7.03–7.10(dt, 1H, J,4.1, 9.1), 7.17–7.25(m, 2H), 7.75–7.76(d, J,1.86). I(m)

5-Bromo-3-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-2-ylamine 365I(n)

5-Bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine(CDCl₃, 300 MHz) δ.1.85–1.95(d, 3H), 4.7–5.0(brs, 2H), 5.9–6.01(q, 1H),6.8–6.95(d, 1H),7.01–7.2(t, 1H), 7.4–7.45(m,1H), 7.8–7.85(d, 1H). I(o)

5-Bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-2-ylamine364 II(a)

5-Bromo-3-(2,6-dichloro-benzyloxy)-pyrazin-2-ylamine >20 (400 MHz,DMSO-d₆) δ 5.45(s,2H), 6.45(s, 2H), 7.50(m, 3H),7.63(s, 1H) 350 II(b)

5-Bromo-3-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-ylamine >20 (300MHz, CDCl₃) δ 7.7(s, 1H),7.23–7.16(m, 1H), 7.09–7.01(m, 1H), 5.53(s,2H), 4.72(s, 2H) 351 II(c)

5-Bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-ylamine1.81/2.67 (400 MHz, DMSO-d₆) δ 1.75(d,3H), 6.26(m, 1H), 6.46(s,2H),7.28(m, 1H), 7.41(m, 1H), 7.52(s, 1H) 365 II(d)

5-Bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-2-methyl-propoxy]-pyrazin-2-ylamine18.1 (400 MHz, DMSO-d₆) δ 0.92(d,3H), 1.17(m, 3H), 2.57(m, 1H),5.75(d,1H), 6.49(s, 2H), 7.24(m, 1H), 7.40(m, 1H), 7.54(s,1H) 393 II(e)

5-Bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine0.24/0.66/1.3 (400 MHz, DMSO-d₆) δ 1.74(d,3H), 6.40(m, 1H), 6.52(brs,2H), 7.30(m, 1H), 7.48(m, 1H),7.56(s, 1H); MS m/z 382 (M + 1). 382II(f)

5-Bromo-3-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-ylamine 366

TABLE 2 Met IC₅₀ MS m/z No. Structure Name (μM) Procedure ¹H-NMR (M + 1)I-1

4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenol  0.279seeexamples (400 MHz, DMSO-d₆) δ 9.36(s, 1H, OH),7.77(s, 1H), 7.54(d,J=5.2 Hz, 2H), 7.43(m, 4H), 6.78(d, J=5.2 Hz, 2H), 5.49(br.s, 2H, NH₂),5.30(s, 2H, CH₂). 362 I-2

3-(2,6-Dichloro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine 0.58 seeexamples (400 MHz, DMSO-d₆) δ 7.81(d, J=1.2 Hz,1H), 7.53(m,3H), 7.48(m, 3H), 6.97(d, 2H), 5.53(br. s 2H, NH₂), 5.31(s,2H, CH₂).4.08(t, 2H), 3.55(t, 4H),2.68(t, 2H), 2.46(t, 4H). 374 I-3

3-(2,6-Dichloro-benzyloxy)-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine 0.59 seeexamples (400 MHz, DMSO-d₆) δ 7.89 (d, J=1.2 Hz, 1H), 7.54(d,J=5.2 Hz, 2H), 7.51(d,J=1.2 Hz, 1H), 7.44(dd, 1H), 7.28(dd, 1H),7.18(m,2H), 6.83(dd, 1H), 5.65(br. s,2H), 5.33(s, 2H), 4.12(t, 2H), 3.55(t,6H),2.88(t, 2H), 2.46(t, 2H) 475 I-4

3-(2,6-Dichloro-benzyloxy)-5-(1H-indol-4-yl)-pyridin-2-ylamine  1.4seeexamples (400 MHz, DMSO-d₆) δ 11.18(s, 1H, NH),7.87(d, 1H), 7.5(d,2H), 7.46(d, 2H),7.36(m, 1H), 7.33(m, 1H), 7.12(t, 1H),7.03(d, 1H),6.49(d, 1H), 5.61(br. s, 2H,NH₂), 5.31(s, 2H, CH₂). 384 I-5

3-[2-Chloro-6-(1H-indol-4-yl)-benzyloxy]-5-(1H-indol-4-yl)-pyridin-2-ylamine 4.71 seeexamples 465 I-6

2-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-pyrrole-1-carboxylicacidtert-butyl ester >20 seeexamples 435 I-7

3-(2,6-Dichloro-benzyloxy)-5-(1H-pyrrol-2-yl)-pyridin-2-ylamine  4.25seeexamples (400 MHz, DMSO-d₆) δ 11.05(s, 1H),7.85(s, 1H), 7.58(s, 1H),7.55(s, 1H),7.50(m, 2H), 6.75(s, 1H), 6.35(s, 1H),6.05(s, 1H), 5.50(br.s, 2H), 5.30(s, 2H). 335 I-8

3-(2,6-Dichloro-benzyloxy)-5-(4-fluoro-phenyl)-pyridin-2-ylamine  8.01seeexamples (400 MHz, DMSO-d₆) δ 7.89(s, 1H),7.69(m, 2H), 7.58(m, 3H),7.48(m, 1H),7.23(m, 2H), 5.70(br. s, 2H), 5.35(s, 2H). 364 I-9

3-(2,6-Dichloro-benzyloxy)-5-phenyl-pyridin-2-ylamine  3.8 seeexamples(400 MHz, DMSO-d₆) δ 7.89(d, J=2 Hz,1H), 7.63(d, J=6.8 Hz, 2H), 7.57(d,J=2 Hz, 1H), 7.54(m, 2H), 7.43(m, 1H), 7.40(m, 2H), 7.26(m, 1H),5.68(br. 5, 2H),5.34(s, 2H). 345 I-10

3-(2,6-Dichloro-benzyloxy)-5-(2-fluoro-phenyl)-pyridin-2-ylamine  6.09seeexamples (400 MHz, DMSO-d₆) δ 7.76(d, 1H), 7.55(m, 2H), 7.54(m 1H),7.46(m. 2H), 7.32(m, 1H), 7.25(m, 2H), 5.78(br. s, 2H),5.28(s, 2H). 364I-11

3-(2,6-Dichloro-benzyloxy)-5-(3-fluoro-phenyl)-pyridin-2-ylamine 13.8seeexamples (400 MHz, DMSO-d₆) δ 7.95(d, 1H), 7.58–7.44(m, 7H), 7.17(m1H), 5.78(br. s, 2H),5.35(s, 2H). 364 I-12

5-(4-Amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine  0.606seeexamples (400 MHz, DMSO-d₆) δ 7.75(d, 1H), 7.54(dd, 4H), 7.47(m, 1H),7.40(d, 1H), 7.29(dd, 2H), 6.60(dd, 2H), 5.44(br. s, 2H),5.31(s, 2H),5.15(br s, 2H). 360 I-13

N-{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide 0.44 seeexamples (400 MHz, DMSO-d₆) δ 9.70(s, 1H),7.86(d, 1H), 7.59(m,1H), 7.56(m, 2H),7.55(m, 1H), 7.45(m, 2H), 7.22(dd, 2H),5.63(br. s, 2H),5.33(s, 2H), 2.95(s, 3H). 439 I-14

N-{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-acetamide >20seeexamples (400 MHz, DMSO-d₆) δ 9.94(s, 1H),7.86(d, 1H), 7.59(m, 1H),7.57(m, 2H),7.54(m, 2H), 7.48(m, 2H), 5.61(br. s, 2H),5.33(s, 2H),2.04(s, 3H). 402 I-15

3-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenol  1.34seeexamples (400 MHz, DMSO-d₆) δ 7.83(s, 1H),7.55(dd, 2H), 7.46(m 2H),7.19(m, 1H),7.10(m, 1H), 7.04(m, 1H), 6.98(m, 1H),6.69(m, 1H), 5.67(br.s, 2H), 5.33(s, 2H). 360 I-16

3-(2,6-Dichloro-benzyloxy)-5-(4-methoxy-phenyl)-pyridin-2-ylamine  6.55seeexamples (400 MHz, DMSO-d₆) δ 7.83(s, 1H),7.62–7.54(m, 4H), 6.97(dd,2H), 6.66(dd, 2H), 5.58(br. s, 2H), 5.33(s, 2H),3.77(s, 3H). 357 I-17

5-(3-Amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine  1.07seeexamples (300 MHz, CDCl₃) δ 7.84(d, 1H), 7.68(m, 1H), 7.45(m, 1H),7.36(t, 1H),7.28(d, 1H), 7.22(m, 1H), 6.93(d, 1H),6.86(d, 1H), 6.64(dd,1H), 5.34(s, 2H),4.73(br s, 2H), 4.12(br s, 2H). 360 I-18

3-(2,6-Dichloro-benzyloxy)-5-(3-trifluoromethoxy-phenyl)-pyridin-2-ylamine >20seeexamples (300 MHz, CDCl₃) δ 7.95(d, 1H), 7.49–7.24(m, 7H), 7.17(m.1H), 5.39(s, 2H),4.81(br s, 2H). 429 I-19

2-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenol  2.16seeexamples (300 MHz, CDCl₃) δ 7.81(d, 1H), 7.66(m, 2H), 7.52(m, 1H),7.37(d, 1H),7.26(m, 3H), 6.99(m, 2H), 5.32(s, 2H),4.77(br s, 2H) 361I-20

3-(2,6-Dichloro-benzyloxy)-5-(2-phenoxy-phenyl)-pyridin-2-ylamine >20seeexamples (300 MHz, CDCl₃) δ 7.88(d, 1H), 7.66(m, 2H), 7.45(m, 3H),7.34(m, 2H),7.26(m, 3H), 7.07(m, 2H), 6.93(, 2H),5.16(s, 2H), 4.66(br s,2H). 437 I-21

3-(2,6-Dichloro-benzyloxy)-5-(3,4-difluoro-phenyl)-pyridin-2-ylamine14.3 seeexamples (300 MHz, CDCl₃) δ 7.89(d, 1H), 7.40(d, 2H), 7.26(m,5H), 5.37(s, 2H),4.80(br s, 2H). 381 I-22

3-(2,6-Dichloro-benzyloxy)-5-(3-isopropyl-phenyl)-pyridin-2-ylamine 15.9seeexamples (300 MHz, CDCl₃) δ 7.96(d, 1H), 7.40–7.15(m, 8H), 5.38(s,2H), 4.73(br s, 2H),2.98(m, 1H), 1.31(d, 6H). 387 I-23

3-(2,6-Dichloro-benzyloxy)-5-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine >20seeexamples (300 MHz, CDCl₃) δ 7.76(d, J=8.7 Hz,1H), 7.69(s, 1H),7.58(t, J=7.3 Hz, 1H),7.47(t, J=7.4 Hz, 1H), 7.38(d, J=7.4 Hz,2H),7.27(m, 2H), 7.17(s, 1H), 5.29(s,2H), 4.78(br s, 2H). 413 I-24

3-(2,6-Dichloro-benzyloxy)-5-(2-methoxy-phenyl)-pyridin-2-ylamine 11.5seeexamples (300 MHz, CDCl₃) δ 7.89(s, 1H), 7.41–7.24(m, 6H), 7.02(m,2H), 5.32(s, 2H), 4.69(br s, 2H), 3.84(s, 3H). 375 I-25

3-(2,6-Dichloro-benzyloxy)-5-(4-trifluoromethyl-phenyl)-pyridin-2-ylamine >20seeexamples (300 MHz, CDCl₃) δ 7.98(d, J=1.8 Hz,1H), 7.66(m, 3H),7.36(m, 3H), 7.29(m,2H), 7.89(s, 1H), 5.38(s, 2H), 4.93(brs, 2H) 413I-26

N-{2-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide >20seeexamples (300 MHz, CDCl₃) δ 8.75 (br s, 1H), 7.70–7.14(m, 9H),5.31(s, 2H), 5.16(br s, 2H),3.16(s, 3H) 438 I-27

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-methanol 2.5 seeexamples (300 MHz, CDCl₃) δ 7.84(d, J=1.8 Hz,1H), 7.66(m, 2H),7.63–7.18(m, 6H), 5.36(s, 2H), 4.75(d, 2H), 4.73(br s, 2H),2.5(br, 1H)375 I-28

5-Benzo[1,3]dioxol-5-yl-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine 8.5 seeexamples (300 MHz, CDCl₃) δ 7.88(d, J=1.5 Hz, 1H),7.37(m, 2H),7.29(m, 2H), 6.99(d, 2H),6.87(d, 1H), 5.99(s, 2H), 5.36(s, 2H), 4.74(brs, 2H) 389 I-29

3-(2,6-Dichloro-benzyloxy)-5-(2-trifluoromethoxy-phenyl)-pyridin-2-ylamine >20seeexamples (300 MHz, CDCl₃) δ 7.82(s, 1H), 7.47–7.25(m, 8H), 5.33(s,2H), 4.82(br s, 2H) 429 I-30

3-(2,6-Dichloro-benzyloxy)-5-(4-methyl-thiophen-2-yl)-pyridin-2-ylamine 3.5 seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.9 Hz,1H), 7.37 d, J=8.5Hz, 2H), 7.29(m, 2H),7.00(d, J=1.1 Hz, 1H), 6.80(s, 1H), 5.34(s,2H),4.80(br s, 2H), 2.28(s, 3H) 365 I-31

5-(2-Benzyloxy-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine >20seeexamples (300 MHz, CDCl₃) δ 7.90(d, J=1.7 Hz,1H), 7.49(d, J=1.7 Hz,1H), 7.31(m, 10H),7.06(m, 2H), 5.06(s, 2H), 4.77(br s, 2H). 451 I-32

3-(2,6-Dichloro-benzyloxy)-5-(3-methoxy-phenyl)-pyridin-2-ylamine  4.01seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.7 Hz,1H), 7.39–7.11(m, 4H),7.13(d, J=7.7 Hz,2H), 7.07(t, J=2.1 Hz, 1H), 6.88(dd,J=8.2 Hz, 2.1 Hz,1H), 5.36(s, 2H),4.78(br s, 2H), 3.87(s, 3H). 375 I-33

3-(2,6-Dichloro-benzyloxy)-5-(1H-indol-2-yl)-pyridin-2-ylamine  7.5seeexamples (300 MHz, CDCl₃) δ 8.47(br s, 1H),8.04(s, 1H), 7.70(d, J=5.5Hz, 1H),7.62–7.11(m, 6H), 6.71(d, J=1.3 Hz, 1H),6.66(dd, J=7.7 Hz, 2.1Hz, 1H), 5.29(s,2H), 4.73(br s, 2H). 384 I-34

5-(4-Benzyloxy-3-fluoro-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine13.5 seeexamples (400 MHz, DMSO-d₆) δ 5.20(s, 2H),5.32(s, 2H), 5.65(s,2H), 7.25(t, 1H),7.33(m, 1H), 7.39(m, 3H), 7.46(m, 3H),7.51(m, 4H),7.88(s, 1H) 469 I-35

4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid 12.8seeexamples (400 MHz, DMSO-d₆) δ 7.98(s, 1H),7.92(d, J=5.6 Hz, 2H),7.75(d, J=4.8 Hz, 2H), 7.55(d, J=5.2 Hz, 1H),7.54(dd, 2H), 7.45(m, 1H),5.8(br.s, 2H), 5.34(s, 2H). 390 I-36

4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-diethylamino-ethyl)-benzamide 0.99 seeexamples (400 MHz, DMSO-d₆) δ 8.45(s, 1H),7.97(d, J=1.2 Hz,1H), 7.86(d, J=5.6 Hz, 2H), 7.73(d, J=5.6 Hz, 2H),7.60(d, J=1.2 Hz, 1H),7.54(d, J=5.2 Hz,2H), 7.44(dd, 1H), 5.77(br. s, 2H), 5.34(s,2H), 3.3(m,4H), 2.6(m, 4H), 0.99(t, 6H) 487 I-37

4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(3-diethylamino-propyl)-benzamide 0.82 seeexamples (400 MHz, DMSO-d₆) δ 8.60(s, 1H),7.95(d, J=1.2 Hz,1H), 7.85(d, J=5.6 Hz, 1H), 7.75(d, J=5.6 Hz, 1H),7.70(d, J=1.2 Hz, 1H),7.60(m, 1H), 7.55(m, 2H), 7.45(m, 2H), 5.70(br. s, 2H), 5.35(s, 2H),3.3(m, 4H), 2.6(m, 4H), 1.7(m,2H), 1.0(t, 6H) 501 I-38

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone 1.02 seeexamples (400 MHz, DMSO-d₆) δ 7.95(d, J=2 Hz,1H), 7.72(dd, J=6,1.6 Hz, 2H), 7.59(d,J=1.6 Hz, 1H), 7.57(d, J=1.2 Hz, 1H),7.55(s, 1H),7.43(dd, J=6, 1.2 Hz, 1H),7.40(dd, J=6, 1.6 Hz, 2H), 5.76(br. s,2H),5.35(s, 2H), 3.6(m, 4H),2.3(m, 4H), 2.2(s, 3H). 471 I-39

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 0.062/0.11/0.2(Ki 0.04) seeexamples (400 MHz, DMSO-d₆) δ 7.96(d,1H),7.72(dd, 2H), 7.59(m, 2H), 7.54(m, 2H),7.47(m, 2H), 5.76(br. s, 2H),5.36(s, 2H),4.35(m, 1H), 3.5(d, 2H), 3.0(m, 4H),1.7–2.0(m, 10H). 525I-40

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 0.21 seeexamples (400 MHz, DMSO-d₆) δ 7.93(d, 1H),7.68(dd, 2H), 7.57(d,1H), 7.54(dd, 2H),7.47(m, 2H), 7.44(m, 1H), 5.74(br. s, 2H),5.34(s, 2H),3.45(m, 1H), 3.3(m,4H), 2.46(m, 2H), 1.95(m, 2H),1.84(m, 4H), 1.63(m,4H). 526 I-41

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone 0.35 seeexamples (400 MHz, DMSO-d₆) δ 7.95(d, 1H),7.70(dd, 2H), 7.55(d,1H), 7.48(dd, 2H),7.41(m, 1H), 7.39(m, 2H), 5.76(br. s, 2H),5.35(s, 2H),3.0(m, 4H), 2.6(m, 4H),2.25(s, 1H), 1.89(m, 4H), 1.66(m, 4H) 525 I-42

{4-(6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone 0.56 seeexamples (400 MHz, DMSO-d₆) δ 7.94(d, 1H),7.71(dd, 2H), 7.70(d,1H), 7.59(dd, 2H),7.55(m, 1H), 7.45(m, 2H), 5.76(br. s, 2H),5.35(s. 2H),4.35(t, 2H), 3.60(m, 1H),3.44(m, 2H), 3.0(m, 2H), 1.68(m, 2H),1.40(m,2H), 1.37(m, 2H) 500 I-43

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone 0.47 seeexamples (400 MHz, DMSO-d₆) δ 7.95(d, 1H),7.75(dd, 2H), 7.57(d,1H), 7.55(dd, 2H),7.48(m, 1H), 7.46(m, 2H), 5.76(br. s, 2H),5.35(s, 2H),3.60(m, 1H), 3.0(m, 2H), 2.2(s, 3H), 2.1(s, 3H), 1.15(m, 2H) 485 I-44

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-methanone 0.65 seeexamples (400 MHz, DMSO-d₆) δ 7.95(m, 1H),7.72(m, 2H), 7.60(m,1H), 7.55(m, 2H),7.46(m, 3H), 5.76(br. s, 2H), 5.35(s, 2H),3.50(m, 3H),3.0(m, 2H), 2.1(s, 3H), 2.05(s, 3H), 1.1(m, 2H) 485 I-45

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-cyclopropylaminomethyl-piperidin-1-yl]-methanone 0.77 seeexamples (400 MHz, DMSO-d₆) δ 7.94(d, 1H),7.77(m, 2H), 7.57(m,2H), 7.55(m, 1H),7.46(dd, 1H), 7.39(m, 2H), 5.79(s, 2H),5.35(s, 2H),4.4(m, 1H), 3.6(m, 1H),2.6–3.0(m, 4H), 1.4–1.8(m, 8H),0.8(m, 2H). 526I-46

4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide 0.2 seeexamples (400 MHz, DMSO-d₆) δ 8.48(m, 1H),7.99(d, 2H), 7.88(m,2H), 7.75(m, 2H),7.61(d, 1H), 7.57(m, 2H), 7.46(dd, 1H),5.79(s, 2H),5.36(s, 2H), 4.8(m, 1H),3.75(m, 1H), 3.44(m, 1H), 3.18(m, 1H),2.53(m,4H), 2.40(m, 1H), 1.67(m, 4H) 515 I-47

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-(3-fluoro-piperidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone 0.42 seeexamples 557 I-48

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-cyclopropyl-piperazin-1-yl)-methanone 1.67 seeexamples 497 I-49

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-{(2R)-2-[(cyclopropylmethyl-amino)-methyl]-pyrrolidin-1-yl}-methanone 0.37 seeexamples (400 MHz, DMSO-d₆) δ 7.92(d, 1H), 7.67(m, 2H), 7.54(m,2H), 7.49(m, 2H), 7.43(m, 2H), 5.73(s, 2H), 5.32(s, 2H), 4.2(m,1H),3.5(m, 1H), 3.28(m, 4H), 2.0–1.7(m,6H), 1.18(m, 4H) 525 I-50

4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-cyclopropylmethyl-N-(2R)-pyrrolidin-2-ylmethyl-benzamide 0.29 seeexamples (400 MHz, DMSO-d₆) δ 8.16(d, 1H), 7.61(d, 1H), 7.38(m,2H), 7.23–7.18(m, 4H),7.09(m, 1H), 5.44(s, 2H), 4.98(s, 2H),4.05(m, 1H),3.2(m, 1H), 3.1(m, 1H),2.93(m, 8H), 2.78(m, 2H), 2.10(m, 4H) 525 I-51

4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-hydroxy-3-pyrrolidin-1-yl-propyl)-N-methyl-benzamide 0.71 seeexamples (400 MHz, DMSO-d₆) δ 7.90(m, 1H), 7.76(m, 1H), 7.63(m,2H), 7.52(d, 2H), 7.50(m, 2H), 7.40(m, 1H), 5.69(s, 2H), 5.30(s,2H),3.70(m, 1H), 2.96(s, 3H), 2.44(m,4H), 2.34(m, 4H), 1.75(m, 4H). 529 I-52

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-{(2S)-2-[(3R)-3-hydroxy-pyrrolidin-1-ylmethyl]-pyrrolidin-1-yl}-methanone 0.53 seeexamples (400 MHz, DMSO-d₆) δ 7.96(d, 1H), 7.70(m, 2H), 7.60(m,1H), 7.57(m, 1H),7.55(m, 3H), 7.46(m, 1H), 5.78(s, 2H),5.37(s, 2H),4.3(m, 1H), 3.6(m, 4H),3.2(m, 4H), 1.9(m, 4H), 1.24(m, 4H). 541 I-53

3-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acid 16seeexamples (400 MHz, DMSO-d₆) δ 8.13(m, 1H), 7.91(d, 1H), 7.98(m, 2H),7.56(dd, 2H),7.54(m, 2H), 7.47(m, 1H), 5.76(s, 2H),5.36(s, 2H) 389 I-54

{3-(6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 2.5 seeexamples (400 MHz, DMSO-d₆) δ 7.93(d, 1H), 7.74(m, 2H), 7.56(m,3H), 7.46(m, 2H),7.36(m, 1H), 5.74(s, 2H), 5.35(s, 2H),4.40(m, 1H),3.40(d, 2H), 3.0(m, 4H),1.7–2.0(m, 10H) 525 I-55

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy}-aceticacid  2.41 seeexamples (400 MHz, DMSO-d₆) δ 7.81(d, 1H), 7.56(m, 2H),7.48(m, 4H), 6.87(m, 2H),5.53(s, 2H), 5.32(s, 2H), 4.33(s, 2H) 419 I-56

2-{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy}-1-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanone 0.53 seeexamples (400 MHz, DMSO-d₆) δ 7.77(d, 1H),7.52(d, 1H), 7.47(m,3H), 7.41(m, 2H),6.88(m, 2H), 5.51(s, 2H), 5.28(s, 2H),4.67(s, 2H),4.20(m, 1H), 3.42(m, 2H),1.82(m, 4H), 1.96(m, 10H). 555 I-57

2-{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenoxy}-1-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanone 0.5 seeexamples (400 MHz, DMSO-d₆) δ 7.82(d, 1H),7.57(d, 1H), 7.52(m,3H), 7.45(m, 2H),6.93(m, 2H), 5.56(s, 2H), 5.33(s, 2H),4.72(s, 2H),4.20(m, 1H), 3.5(m, 2H),2.52(m, 6H), 1.85(m, 4H), 1.66(m, 4H) 555 I-58

3-(2,6-Dichloro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylamine  4.3seeexamples (400 MHz, DMSO-d₆) δ 11.05(s, 1H, NH),7.87(d, 1H), 7.76(m,1H), 7.57(m, 3H),7.40–7.48(m, 2H), 7.34(m, 2H), 6.44(m,1H), 5.49(br. s,2H, NH₂), 5.36(s, 2H, CH₂) 384 I-59

3-(2,6-Dichloro-benzyloxy)-5-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine 1.57 seeexamples (400 MHz, DMSO-d₆) δ 11.35(d, 1H, NH),7.95(s, 1H),7.89(d, 1H), 7.55(m, 4H),7.45(m, 2H), 7.39(dd, 1H), 6.25(m, 1H),5.54(br.s, 2H, NH₂), 5.37(s, 2H, CH₂),3.77(m, 2H), 3.32(m, 2H), 2.82(m,2H),2.80(s, 3H). 480 I-60

3-(2,6-Dichloro-benzyloxy)-5-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine 3.04 seeexamples (400 MHz, DMSO-d₆) δ 10.9(d, 1H, NH),7.90(d, 1H),7.80(s, 1H), 7.55(m, 4H),7.46(m, 2H), 7.32(dd, 1H), 5.50(br. s, 2H,NH₂),5.38(s, 2H, CH₂), 3.32(m, 2H),3.02(m, 2H), 2.90(m, 1H), 2.67(s,3H),2.10(m, 2H), 1.98(m, 2H). 481 I-61

3-(2,6-Dichloro-benzyloxy)-5-(3-morpholin-4-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine 1.19 seeexamples (400 MHz, DMSO-d₆) δ 2.31(m, 4H),3.55(m, 4H), 3.66(s,2H), 5.26(s,2H), 5.45(s, 2H), 7.22(s, 1H), 7.34(m,2H), 7.48(m, 2H),7.57(m, 2H), 7.80(s,1H), 7.85(s, 1H), 10.92(br s, 1H) 483 I-62

3-(2,6-Dichloro-benzyloxy)-5-(3-piperidin-1-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine 1.41 seeexamples (300 MHz, CDCl₃) δ 1.43(m, 2H),1.60(m, 4H), 2.50(m,4H), 3.76(s,2H), 4.65(br s, 2H), 5.40(s, 2H),7.19(s, 1H), 7.27(m, 1H),7.38(m, 5H),7.87(s, 1H), 8.01(d, J=1.7 Hz, 1H),8.17(br s, 1H) 481 I-63

3-(2,6-Dichloro-benzyloxy)-5-(3-pyrrolidin-1-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine 1.34 seeexamples (300 MHz, CDCl₃) δ 1.79(m, 4H),2.62(m, 4H), 3.88(s,2H), 4.64(br s, 2H),5.40(s, 2H), 7.21(d, J=2.3 Hz, 1H),7.26(m, 1H),7.38(m, 5H), 7.84(s, 1H),8.01(d, J=1.8 Hz, 1H), 8.10(br s, 1H) 467 I-64

3-(2,6-Dichloro-benzyloxy)-5-(3-diethylaminomethyl-1H-indol-5-yl)-pyridin-2-ylamine 3.23 seeexamples (300 MHz, CDCl₃) δ 1.13(t, 6H),2.64(q, 4H), 3.88(s,2H), 4.66(br s,2H), 5.37(s, 2H), 7.19(d, J=1.7 Hz,1H), 7.26(m, 1H),7.37(m, 5H),7.86(s, 1H), 8.00(d, J=1.7 Hz, 1H),8.44(br s, 1H) 469 I-65

(1-{5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-(3R)-pyrrolidin-3-yl)-carbamicacid tert-butyl ester  6.3 seeexamples (300 MHz, CDCl₃) δ 1.39(s,9H),2.22(m, 1H), 2.40(m, 1H), 2.58(m, 1H),2.68(m, 1H), 2.99(m, 1H),3.82(d, 1H),3.88(d, 1H), 4.16(m, 1H), 4.65(brs, 2H),4.81(m, 1H), 5.41(s,2H), 7.17(d, J=2.1 Hz,1H), 7.26(m, 1H), 7.38(m, 5H), 7.81(s, 1H),8.00(d,J=1.8 Hz, 1H), 8.09(br s, 1H) 582 I-66

3-(2,6-Dichloro-benzyloxy)-5-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-5-yl]-pyridin-2-ylamine >20seeexamples (300 MHz, CDCl₃) δ 1.13(d, J=6.3 Hz, 6H),1.80(t, J=10.7 Hz,2H), 1.94(br s, 1H), 2.84(d, J=10.5 Hz, 2H), 3.72(m, 4H), 4.68(br s,2H),5.39(s, 2H), 7.16(d, J=2.2 Hz, 1H),7.26(m, 1H), 7.38(m, 5H), 7.89(s,1H),8.10(d, J=1.7 Hz, 1H), 8.32(br s, 1H) 511 I-67

N-(1-{5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-(3R)-pyrrolidin-3-yl)-acetamide 1.79 seeexamples (300 MHz, CDCl₃) δ 1.86(s, 3H), 2.31(m,2H), 2.59(m,1H), 2.70(m, 1H), 2.99(m,1H), 3.82(d, 1H), 3.90(d, 1H), 4.42(m,1H),4.68(br s, 2H), 5.40(s, 2H), 5.91(m, 1H),7.15(d, J=2.2 Hz, 1H),7.26(m,2H), 7.38(m, 5H), 7.82(s, 1H),8.00(d, J=1.8 Hz, 1H), 8.33(br s,1H) 524 I-68

1-(4-{5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-piperazin-1-yl)-ethanone 2.18 seeexamples (300 MHz, CDCl₃) δ 2.07(s, 3H), 2.51(m,4H), 3.44(m,2H), 3.63(m, 2H), 3.78(s,2H), 4.68(br s, 2H), 5.40(s, 2H), 7.17(d,J=2.2Hz, 1H), 7.26(m, 1H), 7.38(m, 5H),7.88(s, 1H), 8.00(d, J=1.8 Hz,1H),8.34(br s, 1H) 524 I-69

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylamineseeexamples 386 I-70

1-(4-{5-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-piperazin-1-yl)-ethanone 0.8 seeexamples (300 MHz, CDCl₃) δ 2.08(s, 3H), 2.49(m,4H), 3.48(m,2H), 3.61(m, 2H), 3.80(s,2H), 4.68(s, 2H), 5.30(s, 2H), 7.02(m,1H),7.20(m, 2H), 7.41(m, 3H), 7.89(s, 1H),8.06(s, 1H), 8.63(s, 1H) 526I-71

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-5-yl]-pyridin-2-ylamine 2.71 seeexamples (300 MHz, CDCl₃) δ 1.37(d, 6H), 1.92(m,2H), 2.95(m,2H), 3.87(m, 4H), 4.68(s, 2H),5.34(s, 2H), 7.08(m, 1H), 7.27(m,2H),7.48(m, 3H), 7.89(s, 1H), 7.98(s, 1H),8.21(br s, 1H) 513 I-72

N-(1-{5-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-1H-indol-3-ylmethyl}-(3S)-pyrrolidin-3-yl)-acetamide 0.95 seeexamples (300 MHz, CDCl₃) δ 1.71(m, 1H), 1.81(s,3H), 2.31(m,2H), 2.48(m, 1H), 2.79(m,2H), 3.11(m, 1H), 3.98(m, 2H), 4.68(s,2H),5.31(s, 2H), 7.06(m, 1H), 7.20(m, 2H),7.45(m, 4H), 7.86(s, 1H),7.98(s, 1H),8.38(s, 1H) 526 I-73

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(3-piperidin-1-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine 0.74 seeexamples .(300 MHz, CDCl₃) δ 1.84(m, 2H), 1.64(m,4H), 2.56(m,4H), 3.80(s, 2H), 4.68(s. 2H),5.30(s, 2H), 7.08(m, 1H), 7.20(m,2H),7.45(m, 3H), 7.86(s, 1H), 7.89(s, 1H),8.49(br s, 1H) 483 I-74

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(3-morpholin-4-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine 1.4 seeexamples (300 MHz, CDCl₃) δ 2.72(m, 4H), 3.80(m,6H), 4.70(s,2H), 5.33(d, 2H), 7.07(m, 1H),7.20(m, 1H), 7.35–7.55(m, 4H), 7.86(s,1H), 8.00(d, 1H), 8.23(s, 1H) 485 I-75

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(3-pyrrolidin-1-ylmethyl-1H-indol-5-yl)-pyridin-2-ylamine 0.7 seeexamples (300 MHz, CDCl₃) δ 1.86(m, 4H), 2.79(m,4H), 4.01(s,2H), 4.63(s, 2H), 5.30(d, 2H),7.05(m, 1H), 7.18(m, 1H), 7.30–7.60(m,4H), 7.80(s, 1H), 8.00(d, 1H),8.64(s, 1H) 469 I-76

5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylicacidethyl ester >20 seeexamples (400 MHz, DMSO-d₆) δ 1.34(t, 3H),4.34(m, 2H), 5.34(s, 2H), 5.58(s, 2H), 7.16(s,1H), 7.52(m, 6H), 7.84(d,2H),11.84(s, 1H) 456 I-77

5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylicacid  1.62 seeexamples (400 MHz, DMSO-d₆) δ 5.46(s, 2H), 5.53(s, 2H),6.66(s, 1H), 7.33(d, 1H), 7.44(m,2H), 7.54(m, 3H), 7.72(s, 1H),7.86(s,1H), 11.12(s, 1H) 428 I-78

{5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-2-yl}-(4-methyl-piperazin-2-yl)-methanone 0.18 seeexamples (400 MHz, DMSO-d₆) δ 2.21(s, 3H), 2.36(m, 4H), 3.74(m,4H), 5.35(s, 2H), 5.53(s,2H), 6.78(s, 1H), 7.50(m, 6H),7.81(s, 1H),7.88(s, 1H), 11.56(s, 1H) 510 I-79

{5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-2-yl}-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-methanone 0.18 seeexamples (400 MHz, DMSO-d₆) δ 1.80(m, 1H), 2.12(m, 1H), 2.21(s,6H), 2.74(m, 1H), 3.25(m,1H), 3.53(m, 1H), 3.78(m, 1H),4.02(m, 1H),5.36(s, 2H),5.54(s, 2H), 6.98(s, 1H), 7.46(m, 3H),7.56(m, 3H), 7.86(m,2H), 11.56(s, 1H) 524 I-80

{5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-2-yl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 0.079 seeexamples (400 MHz, DMSO-d₆) δ 1.80(m, 1H),2.12(m, 1H), 2.21(s,6H), 2.74(m,1H), 3.25(m, 1H), 3.53(m, 1H),3.78(m, 1H), 4.02(m,1H),5.36(s, 2H), 5.54(s, 2H), 8.98(s, 1H),7.46(m, 3H), 7.56(m, 3H),7.88(m, 2H), 11.53(s, 1H) 524 I-81

5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide  1.2 seeexamples (400 MHz, DMSO-d₆)δ 1.68(m, 4H), 2.51(m, 4H), 2.58(t, 2H), 3.39(m, 2H), 7.11(s,1H),7.45(m, 2H), 7.55(m, 3H),7.60(m, 1H), 7.82(s, 1H),7.88(s, 1H), 8.45(t,1H), 11.56(s, 1H) 524 I-82

5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylicacid (2-morpholin-4-yl-ethyl)-amide  1.8 seeexamples (400 MHz, DMSO-d₆)δ 2.41(m, 6H), 3.39(m, 2H), 3.58(m, 4H), 7.11(s, 1H), 7.45(m,2H),7.55(m, 4H), 7.82(s, 1H),7.88(s, 1H), 8.42(t, 1H), 11.52(s, 1H) 540 I-83

(1-{5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carbonyl}--(3S)-pyrrolidin-3-yl)-carbamicacid tert-butyl ester  5 seeexamples (400 MHz, DMSO-d₆) δ 1.38(s,9H),1.64(m, 1H), 1.98(m, 2H), 3.18(m,2H), 3.78(m, 2H), 5.37(s,2H),5.53(s, 2H), 8.92(m, 1H), 7.26(m, 1H),7.48(m, 2H), 7.56(m, 3H),7.61(m, 1H),7.86(m, 2H), 11.52(s, 1H) 596 I-84

{5-(6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indol-2-yl}-[(3S)-amino-pyrrolidin-1-yl]-methanone 0.14 seeexamples (400 MHz, DMSO-d₆) δ 2.20(m, 2H), 2.68(m, 1H), 3.84(m,4H), 5.58(s, 2H), 7.52(m,6H), 7.94(m, 5H), 8.62(m, 2H) 496 I-85

5-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-1H-indole-2-carboxylicacid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide  0.7 seeexamples (400MHz, DMSO-d₆) δ 1.87(m, 4H), 2.37(m, 1H), 2.52(m, 1H), 3.31(m,1H),3.62(m, 4H), 3.46(m, 1H), 3.76(m, 1H),5.38(s, 2H), 5.52(s, 2H),7.14(s, 1H),7.46(m, 2H), 7.56(m, 4H), 7.86(m, 2H),8.48(t, 1H), 11.58(s,1H) 554 I-86

4-(6-Amino-5-benzyloxy-pyridin-3-yl)-phenol  8.7 seeexamples (400 MHz,DMSO-d₆) δ 9.4 (s, 1H), 7.74(d, J=2 Hz, 1H), 7.52 (d, J=7.2 Hz,2H), 7.38(m, 4H), 7.32 (m, 2H), 6.8(d,J=7.2 Hz, 2H), 5.69(s, 2H), 5.22(s, 2H) 293I-87

3-Benzyloxy-5-phenyl-pyridin-2-ylamine seeexamples (400 MHz, DMSO-d₆)7.84(d, 1H), 7.56(d,2H), 7.51(d, 2H), 7.38(m, 5H), 7.31(t, 1H),7.25(t,1H), 5.83(br s, 2H), 5.24(s, 2H) 277 I-88

3-(3-Methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine seeexamples (400 MHz,DMSO-d₆) 7.85(d, 1H), 7.56(m,2H), 7.38(m, 3H), 7.28(m, 2H), 7.08(m,2H),6.86(m, 1H), 5.84(br s, 2H),5.21(s, 2H), 3.75(s, 3H) 307 I-89

3-(2-Chloro-4-fluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine 17seeexamples (400 MHz, DMSO-d₆) δ 7.88(s, 1H),7.79(m, 1H), 7.59(m, 2H),7.51(dd, 1H),7.40(m, 3H), 7.27(m, 2H), 5.84(s, 2H),5.24(s, 2H) 329 I-90

3-(2-Chloro-benzyloxy)-5-phenyl-pyridin-2-ylamine 48% at20 uMseeexamples (400 MHz, DMSO-d₆) δ 7.68(d, 1H),7.73(m, 1H), 7.68(m, 2H),7.50(m, 1H),7.38(m, 5H), 7.26(m, 1H), 5.57(s, 2H),5.30(s, 2H) 311 I-91

3-(2,5-Dichloro-benzyloxy)-5-phenyl-pyridin-2-ylamine 48% at20 uMseeexamples (400 MHz, DMSO-d₆) δ 7.89(d, 1H),7.85(d, 1H), 7.59(m, 2H),7.53(d, 1H),7.46(d, 1H), 7.39(m, 3H), 7.26(m, 1H),5.95(s, 2H), 5.30(s,2H) 345 I-92

3-(2-Chloro-5-trifluoromethyl-benzyloxy)-5-phenyl-pyridin-2-ylamine >20seeexamples (400 MHz, DMSO-d₆) δ 8.15(s, 1H),7.89(d, 1H), 7.76(d, 2H),7.59(m, 2H),7.48(d, 1H), 7.39(m, 2H), 7.26(m, 1H),5.90(s, 2H), 5.36(s,2H) 379 I-93

3-(2,4-Dichloro-5-fluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine >20seeexamples (400 MHz, DMSO-d₆) δ 7.95(d, 1H),7.88(m, 2H), 7.60(m, 2H),7.44(d, 1H),7.39(m, 2H), 7.26(m, 1H), 6.01(s, 2H),5.24(s, 2H) 364 I-94

3-(2-Chloro-3-trifluoromethyl-benzyloxy)-5-phenyl-pyridin-2-ylamine >20seeexamples (400 MHz, DMSO-d₆) δ 8.10(d, 1H),7.89(d, 1H), 7.85(m, 1H),7.60(m, 3H),7.45(d, 1H), 7.39(m, 2H), 7.26(m, 1H),5.93(s, 2H), 5.37(s,2H) 379 I-95

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine  0.64seeexamples (400 MHz, DMSO-d₆) δ 7.89(d, 1H),7.57(m, 4H), 7.40(m, 3H),7.26(m, 1H),5.72(s, 2H), 5.28(s, 2H) 347 I-96

3-(3,4-Dichloro-benzyloxy)-5-phenyl-pyridin-2-ylamine 16.2 seeexamples(400 MHz, DMSO-d₆) δ 7.86(d, 1H),7.84(d, 1H). 7.65(m, 1H), 7.67(m,3H),7.39(m, 3H), 7.26(m, 1H), 5.96(s, 2H),5.24(s, 2H); MS m/z 345 [M +1]. 345 I-97

2-(2-Amino-5-phenyl-pyridin-3-yloxymethyl)-benzonitrile 12.2 seeexamples(400 MHz, DMSO-d₆) δ 7.90(dd, 2H),7.82(d, 1H), 7.75(m, 1H), 7.56(m,3H),7.48(d, 1H), 7.40(m, 2H), 7.26(m, 1H),5.85(s, 2H), 5.39(s, 2H) 302I-98

3-(2-Chloro-6-fluoro-3-methyl-benzyloxy)-5-phenyl-pyridin-2-ylamine  7.6seeexamples (400 MHz, DMSO-d₆) δ 7.88(d, 1H),7.61(m, 2H), 7.53(d, 1H),7.43(m, 3H),7.25(m, 2H), 5.65(s, 2H), 5.27(s, 2H),2.34(s, 3H) 342 I-99

5-Phenyl-3-(2,3,6-trifluoro-benzyloxy)-pyridin-2-ylamine  3.9seeexamples (400 MHz, DMSO-d₆) δ 7.89(d, 1H),7.61(m, 3H), 7.52(d, 1H),7.40(m, 2H),7.25(m, 2H), 5.75(s, 2H), 5.26(s, 2H) 331 I-100

3-(2,6-Difluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine  9.3 seeexamples(400 MHz, DMSO-d₆) δ 7.88(d, 1H),7.61(m, 2H), 7.51(m, 2H), 7.40(m,2H),7.26(m, 1H), 7.18(m, 2H), 5.69(s, 2H),5.23(s, 2H) 314 I-101

3-(2,6-Difluoro-3-methyl-benzyloxy)-5-phenyl-pyridin-2-ylamine 12seeexamples (400 MHz, DMSO-d₆) δ 7.88(d, 1H),7.60(m, 2H), 7.51(d, 1H),7.40(m, 3H),7.27(m, 1H), 7.07(m, 1H), 5.68(s, 2H),5.21(s, 2H) 328 I-102

3-(3-Chloro-2,6-difluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine  9.6seeexamples (400 MHz, DMSO-d₆) δ 7.88(d, 1H),7.74(m, 1H), 7.61(m, 2H),7.51(d, 1H),7.40(m, 2H), 7.27(m, 2H), 5.76(s, 2H),5.26(s, 2H) 347 I-103

3-(2-Chloro-8-fluoro-benzyloxy)-5-phenyl-pyridin-2-ylamine  7.91seeexamples (400 MHz, DMSO-d₆) δ 7.88(d, 1H),7.61(m, 2H), 7.52(d, 1H),7.49(m, 1H),7.40(m, 3H), 7.30(m, 2H), 5.67(s, 2H),5.27(s, 2H) 329 I-104

3-(3-Fluoro-4-methoxy-benzyloxy)-5-phenyl-pyridin-2-ylamine 15seeexamples (400 MHz, DMSO-d₆) δ 7.84(d, 1H),7.56(m, 1H), 7.43(d, 1H),7.38(m, 3H),7.26(m, 2H), 7.10(m, 2H), 5.58(s, 2H),5.15(s, 2H) 325 I-105

N-[3-(2-Amino-5-phenyl-pyridin-3-yloxymethyl)-phenyl]-methanesulfonamide >20seeexamples (400 MHz, DMSO-d₆) δ 9.76(s, 1H),7.85(d, J=1.8 Hz, 1H),7.57(d, 2H),7.38(m, 5H), 7.28(m, 2H), 7.15(d, 1H),5.85(br s, 2H),5.22(s, 2H), 2.96(s, 3H) 370 I-106

5-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-3-(3-nitro-benzyloxy)-pyridin-2-ylamine12.6 seeexamples (DMSO-d₆) δ 2.50(m, 4H), 2.69(m,2H), 3.57(t, 4H),4.09(t, 2H), 5.37(s, 2H), 5.85(s, 2H), 6.96(d, 2H),7.38(d, 1H), 7.48(d,2H), 7.69(t, 1H),7.81(d, 1H), 8.01(m, 1H), 8.17(m,1H), 8.36(m, 1H) 451I-107

5-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-3-(naphthalen-1-ylmethoxy)-pyridin-2-ylamine 7.7 seeexamples (DMSO-d₆) δ 2.50(m, 4H), 2.69(t,2H), 3.57(t, 4H),4.10(t, 2H), 5.66(s, 2H), 5.67(s, 2H), 6.97(d, 2H),7.49–7.61(m, 5H),7.78–7.82(m, 2H),7.88–7.98(m, 2H), 8.20(dd, 1H) 456 I-108

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine 0.21 seeexamples (400 MHz, CDCl₃) δ 2.60(m, 4H),2.83(t, 2H), 3.74(t,4H), 4.16(t, 2H), 4.63(s, 2H), 5.27(d, 2H), 6.98(d, 2H), 7.02–7.10(m,1H), 7.16–7.22(m, 1H), 7.30(2,2H), 7.44(d, 2H), 7.91(d, 1H) 476 I-109

2-{2-Amino-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-3-yloxy}-N-(4-isopropyl-phenyl)-2-phenyl-acetamide >20seeexamples (400 MHz, DMSO-d₆) δ 1.15(d, 6H),2.50(m, 4H), 2.68(m, 2H),2.77–2.89(m, 1H), 3.57(t, 6H), 4.08(t, 2H),6.15(s, 1H), 6.20(s, 2H),6.93(d, 2H),7.17(d, 1H), 7.30–7.44(m, 3H),7.48(d, 2H), 7.68(d, 2H),7.79(d, 1H) 568 I-110

3-(5-Chloro-benzo[b]thiophen-3-ylmethoxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine 2.4 seeexamples (400 MHz, DMSO-d₆) δ 2.50(m, 4H),2.70(m, 2H), 3.58(t,4H), 4.11(t, 2H), 5.46(s, 2H), 5.82(s, 2H), 6.98(d, 2H), 7.43(dd, 1H),7.50–7.56(m, 3H) 7.80(d, 1H),8.05(d, 1H), 8.11(d, 1H), 8.16(s, 1H) 496.5I-111

{4-[6-Amino-5-(4-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 1.51 seeexamples (400 MHz, DMSO-d₆) δ 7.94(s, 2H),7.71(m, 4H), 7.44(m,3H), 5.92(s, 2H),5.36(s, 2H), 4.21(m, 1H), 3.52(m, 2H),2.69(m, 5H),1.96(m, 2H), 1.84(m, 3H),1.68(m, 4H) 543 I-112

{4-[6-Amino-5-(2-fluoro-6-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 0.15 seeexamples (400 MHz, DMSO-d₆) δ 7.94(s, 1H),7.69(m, 5H), 7.59(s,1H), 7.50(m, 2H),5.72(s, 2H), 5.26(s, 2H), 4.16(m, 1H),3.47(m, 2H),2.63(m, 5H), 1.96(m, 2H),1.86(m, 3H), 1.68(m, 4H) 543 I-113

{4-(6-Amino-5-(5-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 1.27 seeexamples (400 MHz, DMSO-d₆) δ 7.95(s, 1H),7.85(m, 2H), 7.63(m,2H), 7.48(m, 2H),7.42(m, 2H), 6.04(s, 2H), 5.36(s, 2H),4.16(m, 1H),3.44(m, 2H), 2.62(m, 5H),1.96(m, 2H), 1.85(m, 3H), 1.66(m, 4H) 543 I-114

(4-{6-Amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 0.33 seeexamples (400 MHz, DMSO-d₆) δ 7.85(d, 1H),7.81(s, 1H), 7.76(m,2H), 7.41(m, 5H),7.03(s, 1H), 6.16(s, 2H), 5.81(m, 1H),4.10(m, 1H),3.41(m, 2H), 2.59(m, 5H),1.94(m, 2H), 1.82(m, 3H), 1.64(d, 3H),1.48(m,4H) 539 I-115

{4-[6-Amino-5-(2-bromo-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 1.75 seeexamples (400 MHz, DMSO-d₆) δ 7.74(s, 1H),7.68(m, 3H), 7.45(m,5H), 7.31(m, 1H),5.92(s, 2H), 5.25(s, 2H), 4.16(m, 1H),3.43(m, 2H),2.62(m, 5H), 1.94(m, 2H),1.82(m, 3H), 1.65(m, 4H) 537 I-116

{4-(6-Amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 0.025 seeexamples (400 MHz, DMSO-d₆) δ 7.92(s, 1H),7.66(m, 4H), 7.46(m,4H), 5.89(s, 2H),5.39(s, 2H), 4.19(m, 1H), 3.50(m, 2H),2.54(m, 5H),1.95(m, 2H), 1.83(m, 3H),1.64(m, 4H) 543 I-117

{4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 0.063 seeexamples (400 MHz, DMSO-d₆) δ 7.95(d, 1H),7.69(d, 2H), 7.58(m,2H), 7.50(d, 2H),7.40(m, 1H), 5.81(s, 2H), 5.29(s, 2H),4.35(m, 1H),3.5(d, 2H), 2.87(d, 2H),2.71(d, 2H), 1.7–2.0(m, 10H) 527 I-118

4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl  3.79seeexamples (400 MHz, DMSO-d₆) δ 9.38(s, 1H),7.77(d, J=2 Hz 1H), 7.52(m,2H),7.40(m, 3H), 7.17(m, 2H), 6.79(m,2H), 5.53(br. s, 2H), 5.20(s, 2H)329 I-119

3-(2,6-Difluoro-benzyloxy)-5-(1H-indol-4-yl)-pyridin-2-ylamine  5.8seeexamples (400 MHz, DMSO-d₆) δ 7.81(d, J=2 Hz, 1H), 7.51(m, 3H),7.45(d,J=2 Hz, 1H), 7.17(m, 2H), 6.98(m, 2H), 5.58(s, 2H), 5.21(s,2H),4.10(t, 2H), 3.57(t, 4H),2.69(t, 2H), 2.48(t, 4H) 442 I-120

3-(2,6-Difluoro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamineseeexamples (400 MHz, DMSO-d₆) δ 11.18(s,1H), 7.86(d, J=2 Hz, 1H),7.52(m, 1H), 7.44(d, J=2 Hz, 1H),7.36(dd, 1H), 7.34(m, 1H), 7.18(m,2H),7.13(dd, 1H), 7.02(dd, 1H),6.49(m, 1H), 5.66(s, 2H), 5.22(s, 2H) 352I-121

4-(6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acidseeexamples (400 MHz, DMSO-d₆) δ 12.85(s,1H), 7.94(d, J=2 Hz, 1H),7.89(dd, 2H), 7.71(dd, 2H), 7.55(d,J=2 Hz, 1H), 7.47(m, 1H), 7.13(m,2H),5.83(s, 2H), 5.19(s, 2H) 357 I-122

{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone1.21 seeexamples (400 MHz, DMSO-d₆) δ 7.94(d,1H), 7.68(dd, 2H), 7.56(m,1H),7.51(m, 3H), 7.18(m, 2H), 5.79(s, 2H), 5.29(s, 2H), 3.48(m,1H),2.65(m, 4H), 2.48(d,2H), 1.86(m, 10H) 493 I-123

{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 1.36 seeexamples (400 MHz, DMSO-d₆) δ 7.94(d,1H), 7.68(dd, 2H), 7.56(m,1H),7.51(m, 3H), 7.18(m, 2H), 5.78(s, 2H), 5.24(s, 2H), 4.8(m,1H),3.5(m, 2H), 2.52(d, 4H), 1.86(m, 10H) 493 I-124

{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-aceticacidethyl ester seeexamples (400 MHz, DMSO-d₆) δ 7.81(d,J=2 Hz, 1H),7.52(m, 3H), 7.18(m,1H), 6.96(m, 2H), 5.70(br. s,2H), 5.23(s, 2H),4.79(s, 2H), 2.68(q,4H), 1.21(t, 3H) 415 I-125

{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-aceticacid 14.7 seeexamples (400 MHz, DMSO-d₆) δ 7.79(d,1H), 7.51(m, 1H),7.47(m, 1H), 7.44(m, 2H), 7.17(m, 2H), 7.05(m,2H), 5.55(br. s, 2H),5.21(s, 2H),4.25(s, 2H) 387 I-126

2-{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-1-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanone 3.58 seeexamples (400 MHz, DMSO-d₆) δ 7.81(d,1H), 7.51(m, 3H), 7.45(d,1H), 7.18(m, 2H), 6.80(m, 2H), 5.65(s,2H), 5.22(s, 2H), 4.80(dd, 2H),4.29(m,1H), 3.53(m, 2H), 3.20(m, 4H),1.93(m, 10H) 523 I-127

2-{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenoxy}-1-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-ethanone 5.43 seeexamples (400 MHz, DMSO-d₆) δ 7.81(d,1H), 7.52(m, 3H), 7.46(d,1H), 7.18(m, 2H), 7.00(m, 2H), 5.68(s,2H), 5.22(s, 2H), 4.80(dd, 2H),4.60(m,1H), 3.53(m, 2H), 3.19(m, 4H),1.96(m, 10H) 523 I-128

4-[6-Amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenol  3.99seeexamples (400 MHz, DMSO-d₆) δ 9.38(s,1H), 7.77(d, 1H), 7.50(m, 1H),7.42(m, 4H), 7.39(m, 1H), 6.80(m,2H), 5.50(s, 2H), 5.24(s, 2H) 345 I-129

4-[6-Amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenol 19seeexamples (DMSO-d₆) δ 5.21(s, 2H), 5.67(s,2H), 6.80(d, 2H), 7.26(t,1H), 7.34(s, 1H),7.41(d, 2H), 7.50(d, 1H), 7.79(m, 2H),9.38(s, 1H) 345I-130

4-[6-Amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenol 9/>20seeexamples (DMSO-d₆) δ 5.21(s, 2H), 5.71(s, 2H),6.81(d, 2H), 7.40(m,5H), 7.74(m, 2H),9.38(s, 1H) 361 I-131

2-[2-Amino-5-(4-hydroxy-phenyl)-pyridin-3-yloxymethyl]-benzonitrile 19seeexamples (DMSO-d₆) δ 5.35(s, 2H), 5.68(s,2H), 6.77(d, 2H), 7.41(m,3H), 7.54(t, 1H),7.78(m, 3H), 7.92(d, 1H), 9.38(s, 1H) 318 I-132

4-[6-Amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenol  3.67seeexamples (400 MHz, DMSO-d₆) δ 5.32(s, 2H),5.68(s, 2H), 6.78(d, 2H),7.26(s, 1H),7.36(d, 2H), 7.57(t, 1H), 7.72(t, 1H),7.78(m, 2H), 7.86(m,1H), 9.38(s, 1H) 361 I-133

4-[6-Amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenol 13.8 seeexamples(DMSO-d₆) δ 5.25(s, 2H), 5.69(s,2H), 6.78(d, 2H), 7.38(m, 5H),7.50(m,1H), 7.71(m, 1H), 7.78(s, 1H), 9.38(s, 1H) 326 I-134

4-[6-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenol  4seeexamples (DMSO-d₆) δ 1.26(s, 9H), 5.16(s,2H), 5.63(s, 2H), 6.78(d,2H), 7.40(m,7H), 7.72(s, 1H), 9.36(s, 1H) 349 I-135

N-{4-[6-Amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide 4.18 seeexamples (DMSO-d₆) δ 2.98(s, 3H), 5.36(s,2H), 5.82(s, 2H),7.24(d, 2H), 7.42(s,1H), 7.58(m, 3H), 7.75(t, 1H),7.89(m, 3H), 9.70(s,1H) 393 I-136

2-[2-Amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-benzamide >20seeexamples (DMSO-d₆) δ 2.88(s, 3H), 5.37(s,2H), 5.75(s, 2H), 7.15(d,2H), 7.30(s,1H), 7.48(m, 6H), 7.20(d, 1H),7.80(s, 1H), 7.90(s, 1H) 413I-137

2-[2-Amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-benzoicacid >20 seeexamples (DMSO-d₆) δ 3.00(s, 3H), 5.65(s,2H), 7.26(d, 2H),7.47(m, 3H), 7.60(m,4H), 7.72(m, 1H), 7.82(s, 1H),7.94(d, 1H), 9.84(s,1H) 414 I-138

N-(4-{6-Amino-5-[2-(4-methyl-piperazine-1-carbonyl)-benzyloxy]-pyridin-3-yl}-phenyl)-methanesulfonamide >20seeexamples (DMSO-d₆) δ 2.08(s, 3H), 2.26(m, 2H),2.96(s, 3H), 3.15(m,2H), 3.36(m, 2H),3.59(m, 2H), 5.17(br s, 2H),5.78(s, 2H), 7.23(d, 2H),7.28(m, 1H),7.36(s, 1H), 7.43(m, 2H), 7.57(m, 4H),7.84(s, 1H) 496 I-139

2-[2-Amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-N-(2-hydroxy-ethyl)-benzamide >20seeexamples (DMSO-d₆) δ 2.96(s, 3H), 3.28(m,2H), 3.46(m, 2H), 4.70(s,1H), 5.30(s,2H), 5.78(s, 2H), 7.23(d,2H), 7.32(s, 1H), 7.39(m,1H),7.47(m, 2H), 7.53(m, 2H), 7.62(d, 1H),7.83(s, 1H), 8.37(t, 1H),9.72(br s, 1H) 457 I-140

2-[2-Amino-5-(4-methanesulfonylamino-phenyl)-pyridin-3-yloxymethyl]-N-isobutyl-benzamide >20seeexamples (DMSO-d₆) δ 0.84(d, 6H), 1.78(m,1H), 2.82(s, 3H), 3.03(t,2H), 5.28(s,2H), 5.72(s, 2H), 7.12(d,2H), 7.24(s, 1H), 7.42(m,5H),7.62(d, 1H), 7.79(s, 1H), 8.41(t, 1H),9.68(s, 1H) 469 I-141

4-[6-Amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acidseeexamples (400 MHz, DMSO-d₆) δ 5.25(s, 2H,CH₂), 5.82(br s, 2H,NH₂),6.30–8.00(muitiplets, 9H, aromatic) 373 I-142

{4-[6-Amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 0.63 seeexamples (300 MHz, CDCl₃) δ 7.96(d, 1H),7.57(m, 4H), 7.10(m,3H), 7.04(t, 1H),5.30(s, 2H), 4.83(s, 2H), 4.45(m, 1H),3.40(m, 2H),2.90(m, 4H), 2.2–1.5(m, 10H) 509 I-143

{4-[6-Amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone13 seeexamples (300 MHz, CDCl₃) δ 7.96(d, 1H),7.57(m, 4H), 7.10(m, 3H),7.04(t, 1H),5.30(s, 2H), 4.83(s, 2H), 4.45(m, 1H),3.40(m, 2H), 2.90(m,4H), 2.2–1.5(m, 10H) 509 I-144

{4-[6-Amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone 1.7 seeexamples (300 MHz, CDCl₃) δ 7.94(s, 1H),7.58(m, 4H), 7.36(m,3H), 7.05(t, 1H),5.30(s, 2H), 5.07(s, 2H), 3.9(m, 1H),3.6(m, 2H), 3.4(m,1H), 3.0(m, 1H),2.37(s, 3H), 2.27(s, 3H), 1.8(m, 2H) 470 I-145

{4-[6-Amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone 0.63 seeexamples 441 I-146

{4-[6-Amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone 1.94 seeexamples (300 MHz, CDCl₃) δ 7.93(d, J=1.7 Hz,1H), 7.56(d, J=8.1Hz, 2H), 7.48(d,J=8.1 Hz, 2H), 7.28(m, 3H), 7.07(t, J=8.8 Hz), 5.30(s,2H), 5.05(br s, 2H),375(m, 4H), 2.48(m, 4H), 2.34(s, 3H) 455 I-147

1-(4-{4-(6-Amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoyl}-piperazin-1-yl)-ethanone 1.45 seeexamples (300 MHz, CDCl₃) δ 7.91(d, J=1.7 Hz,1H), 7.58(d, J=8.2Hz, 2H), 7.50(d,J=8.2 Hz, 2H), 7.35(m, 3H), 7.08(t, J=8.2 Hz), 5.42(brs, 2H), 5.32(s, 2H),3.60(m, 8H), 2.14(s, 3H) 484 I-148

4-[6-Amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide 6.4 seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.7 Hz, 1H), 7.85(d, J=8.2Hz, 2H), 7.65(d, J=8.2 Hz, 2H), 7.30(m, 2H), 7.24(d, J=1.7 Hz, 1H),7.08(m, 1H), 6.95(br t,1H), 5.32(s, 2H), 5.06(br s, 2H), 3.82(m,4H),3.64(m, 2H), 2.76(m, 2H),2.65(m, 4H) 485 I-149

4-[6-Amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide 5.6 seeexamples (300 MHz, CDCl₃) δ 8.02(br t, 1H),7.95(d, J=1.7 Hz,1H), 7.90(d, J=8.3 Hz,2H), 7.59(d, J=8.3 Hz, 2H), 7.39(d, J=1.7 Hz, 1H),7.30(m, 2H), 7.08(m, 1H),6.95(br t, 1H), 5.32(s, 2H), 5.10(br s,2H),3.78(m, 4H), 3.62(m, 2H), 2.64(m, 6H),1.87(m, 2H) 499 I-150

4-[6-Amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-benzoic acid seeexamples(400 MHz, DMSO-d₆) δ 5.30(s, 2H,CH₂), 5.95(br s, 2H,NH₂),7.35–7.95(multiplets, 10H, aromatic). 353(M − 1) I-151

{4-[6-Amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 0.87 seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.6 Hz, 1H), 7.52(m, 6H),7.25(m, 2H),7.21(d, J=1.6 Hz, 1H), 5.26(s, 2H),4.88(br s, 2H), 4.32(m,1H), 3.52(m, 2H),2.89(m, 4H), 2.2–1.5(m, 10H). 491 I-152

{4-[6-Amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 2.3 seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.6 Hz, 1H), 7.52(m, 6H),7.25(m, 2H),7.21(d, J=1.6 Hz, 1H), 5.26(s,2H), 4.88(br s, 2H), 4.32(m,1H),3.52(m, 2H), 2.89(m, 4H), 2.2–1.5(m, 10H). MS m/z 491 [M + 1]. 491I-153

{4-[6-Amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone12.7 seeexamples (300 MHz, CDCl₃) δ 7.95(s, 1H),7.53(m, 6H), 7.33(m,2H), 7.27(s, 1H),5.26(s, 2H), 4.94(br s, 2H), 3.90(m, 1H),3.60(m, 2H),3.45(m, 1H), 2.85(m, 1H),2.32(s, 3H), 2.23(s, 3H), 1.89(m, 2H) 451 I-154

{4-[6-Amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone 1.44 seeexamples 423 I-155

{4-[6-Amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone 1.5 seeexamples (300 MHz, CDCl₃) δ 7.98(d, J=1.8 Hz, 1H), 7.47(m, 6H),7.32(m, 2H),7.21(d, J=1.8 Hz, 1H), 5.26(s, 2H),4.86(br s, 2H), 3.95(m,4H),2.55(m, 4H), 2.30(m, 1H), 1.95(m,2H), 1.76(m, 4H), 1.52(m, 2H). 491I-156

{4-[6-Amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone 2.1 seeexamples (300 MHz, CDCl₃) δ 7.94(d, J=1.8 Hz, 1H), 7.49(m, 6H),7.32(m, 2H),7.21(d, J=1.8 Hz, 1H), 5.27(s, 2H),4.00(br s, 2H), 3.80(m,4H),2.50(m, 4H), 2.35(s, 3H) 437 I-157

1-(4-{4-[6-Amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-benzoyl}-piperazin-1-yl)-ethanone 3.8 seeexamples (300 MHz, CDCl₃) δ 7.95(d, J=1.8 Hz, 1H), 7.51(m, 6H),7.33(m, 2H),7.21(d, J=1.8 Hz, 1H), 5.27(s, 2H),4.94(br s, 2H), 3.65(m,8H),2.14(s, 3H) 465 I-158

4-[6-Amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide 8.9 seeexamples (300 MHz, CDCl₃) δ 7.95(d, J=1.8 Hz, 1H), 7.84(d, J=8.3Hz, 2H),7.55(d, J=8.3 Hz, 2H), 7.51(m, 1H),7.43(m, 1H), 7.34(m, 2H),7.24(d,J=1.8 Hz, 1H), 7.01(br t, 1H), 5.27(s, 2H),5.18(br s, 2H),3.77(m, 4H), 3.61(m, 2H),3.25(m, 2H), 2.70(m, 2H), 2.60(m, 4H) 467 I-159

4-[6-Amino-5-(2-chloro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide 4.5 seeexamples (300 MHz, CDCl₃) δ 7.95(d, J=1.8 Hz, 1H), 7.84(d, J=8.3Hz, 2H),7.55(d, J=8.3 Hz, 2H), 7.51(m, 2H),7.43(m, 1H), 7.34(m, 2H),7.24(d,J=1.8 Hz, 1H), 5.27(s, 2H), 4.97(br s,2H), 3.75(m, 4H), 3.59(m,2H),3.25(m, 2H), 2.57(m, 4H), 1.83(m, 2H). 481 I-160

4-[6-Amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-benzoic acid seeexamples(400 MHz, DMSO-d₆) δ 5.35(s, 2H,CH₂), 5.95(br s, 2H,NH₂),7.50–8.00(multiplets, 10H, aromatic 346 I-161

2-{2-Amino-5-[4-((2R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile 1.22 seeexamples (300 MHz, CDCl₃) δ 7.99(d, J=1.6 Hz, 1H), 7.76(d,J=7.5 Hz, 2H),7.50(m, 6H), 7.24(d, J=1.6 Hz,1H), 5.35(s, 2H), 4.88(br s,2H),4.46(m, 1H), 3.52(m, 2H), 3.24(m, 4H),2.2–1.5(m, 10H) 482 I-162

2-{2-Amino-5-[4-((2S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile 2 seeexamples ¹H NMR(300 MHz, CDCl₃) δ 7.99(d, J=1.6 Hz, 1H), 7.76(d,J=7.5 Hz, 2H),7.50(m, 6H), 7.24(d, J=1.6 Hz, 1H), 5.35(s, 2H), 4.88(brs, 2H), 4.46(m, 1H),3.52(m, 2H), 3.24(m, 4H), 2.2–1.5(m, 10H). 482 I-163

2-{2-Amino-5-[4-((3S)-3-dimethylamino-pyrrolidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile >20seeexamples (300 MHz, CDCl₃) δ 7.98(s, 1H),7.76(d, J=7.6 Hz, 2H),7.50(m, 6H),7.26(s, 1H), 5.38(s, 2H), 4.99(br s, 2H),3.90(m, 1H),3.60(m, 2H), 3.45(m, 1H),2.85(m, 1H), 2.32(s, 3H),2.23(s, 3H), 1.89(m,2H) 442 I-164

2-{2-Amino-5-[4-((3S)-3-amino-pyrrolidine-1-carbonyl-phenyl]-pyridin-3-yloxymethyl}-benzonitrole 2.05 seeexamples (300 MHz, CDCl₃) δ 7.98(d, J=1.4 Hz, 1H), 7.76(d,J=7.5 Hz,2H), 7.50(m, 6H), 7.24(d, J=1.4 Hz, 1H), 5.35(s, 2H), 4.91(brs,2H), 3.70(m, 4H), 2.15(m, 1H),2.23(s, 2H), 1.25(m, 1H),1.05(m, 1H) 414I-165

2-{2-Amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile 3.9 seeexamples (300 MHz, CDCl₃) δ 7.97(d, J=1.7 Hz, 1H), 7.76(d, J=7.5Hz,2H), 7.66(m, 2H), 7.51(m, 2H),7.46(m, 2H), 7.23(d, J=1.4 Hz,1H),5.35(s, 2H), 4.88(br s, 2H),3.95(m, 4H), 2.55(m, 4H), 2.30(m, 1H),1.95(m, 2H), 1.76(m, 4H),1.52(m, 2H) 482 I-166

2-{2-Amino-5-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzonitrile 3.2 seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.8 Hz, 1H), 7.76(d, J=7.5Hz,2H), 7.66(m, 2H), 7.51(m, 2H),7.48(m, 2H), 7.24(d, J=1.4 Hz,1H),5.35(s, 2H), 5.01(br s, 2H),3.65(m, 4H), 2.45(m, 4H), 4H),2.36(s,3H) 428 I-167

2-{5-[4-(4-Acetyl-piperazine-1-carbonyl)-phenyl]-2-amino-pyridin-3-yloxymethyl}-benzonitrile 5.7 seeexamples (300 MHz, CDCl₃) δ 7.95(d, J=1.7 Hz, 1H), 7.76(d, J=7.5Hz,2H), 7.66(m, 2H), 7.54(m, 2H),7.50(m, 2H), 7.26(d, J=1.4 Hz,1H),5.36(s, 2H), 5.27(br s, 2H),3.65(m, 8H), 2.14(s, 3H) 456 I-168

4-[6-Amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide10.8 seeexamples (300 MHz, CDCl₃) δ 7.99(d, J=1.8 Hz,1H), 7.82(d, J=8.3Hz, 2H), 7.74(m, 1H),7.66(m, 2H), 7.55(m, 3H), 7.25(d, J=1.8Hz, 1H),6.18(d, J=8.0 Hz, 1H), 5.35(s,2H), 4.88(brs, 2H), 4.05(m, 1H),2.96(m,1H), 2.46(s, 3H), 2.40(m, 1H), 2.05(m,1H), 1.79(m, 1H), 1.65(m,2H),0.95(m, 2H) 442 I-169

4-[6-Amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide 8.6 seeexamples (300 MHz, CDCl₃) δ 7.98(d, J=1.8 Hz, 1H), 7.85(d, J=8.4Hz,2H), 7.76(d, J=7.4 Hz, 1H),7.66(m, 2H), 7.57(m, 3H), 7.27(d,J=1.8 Hz,1H), 7.06(m, 1H), 5.36(s,2H), 5.14(br s, 2H), 3.78(m,4H), 3.63(m, 2H),2.73(m,2H), 2.63(m, 4H) 458 I-170

4-[6-Amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide17.3 seeexamples (300 MHz, CDCl₃) δ 8.01(d, J=1.7 Hz, 1H), 7.87(d, J=8.4Hz,2H), 7.76(d, J=7.5 Hz, 1H),7.67(m, 1H), 7.56(d, J=8.4 Hz, 2H),7.45(m,3H), 7.27(d, J=1.8 Hz, 1H), 5.36(s, 2H), 4.89(br s, 2H), 3.74(m,4H),3.60(m, 2H), 2.57(m, 6H), 1.82(m, 2H) 472 I-171

4-[6-Amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-benzoic acidseeexamples (400 MHz, DMSO-d₆) δ 5.35(s, 2H,CH₂), 5.90(br s, 2H,NH₂),7.30–8.00(multiplets, 9H, aromatic) 389 I-172

{4-(6-Amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone0.61 seeexamples (300 MHz, CDCl₃) δ 7.97(d, J=1.7 Hz, 1H), 7.47(m, 6H),7.30(dd, J=2.0 Hz, J=8.3 Hz, 1H), 7.18(d, J=1.7 Hz,1H), 5.21(s, 2H),4.85(br s, 2H), 4.42(m,1H), 3.50(m, 2H), 2.84(m, 4H), 2.2–1.5(m, 10H)527 I-173

{4-[6-Amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone0.66 seeexamples (300 MHz, CDCl₃) δ 7.97(d, J=1.7 Hz, 1H), 7.47(m, 6H),7.30(dd, J=2.0 Hz, J=8.3 Hz, 1H), 7.18(d, J=1.7 Hz,1H), 5.21(s, 2H),4.85(br s, 2H), 4.42(m,1H), 3.50(m, 2H), 2.84(m, 4H), 2.2–1.5(m, 10H)527 I-174

{4-[6-Amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone 0.8 seeexamples (300 MHz, CDCl₃) δ 7.95(s, 1H),7.50(m, 6H), 7.30(dd,J=1.9 Hz, J=8.3 Hz, 1H), 7.20(s, 1H), 5.21(s, 2H), 5.07(br s, 2H),3.90(m, 1H), 3.62(m,2H), 3.45(m, 1H), 2.85(m, 1H),2.32(s, 3H), 2.23(s,3H), 1.89(m, 2H) 486 I-175

{4-[6-Amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone 1.2 seeexamples 458 I-176

{4-[6-Amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone 0.85 seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.8 Hz, 1H), 7.71(d,J=3.5 Hz, 1H),7.50(m, 5H), 7.30(dd, J=2.0 Hz, J=8.3 Hz,1H), 7.18(d,J=1.8 Hz, 1H), 5.22(s, 2H),4.83(br s, 2H), 4.23(m, 2H), 2.78(m,2H),1.95(m, 2H), 1.76(m, 3H), 1.25 (m,4H), 0.85(m, 4H) 525 I-177

{4-[6-Amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone 0.79 seeexamples (300 MHz, CDCl₃) δ 7.95(s, 1H),7.50(m, 6H), 7.30(dd,J=1.9 Hz, J=8.3 Hz,1H), 7.20(s, 1H), 5.21(s, 2H), 5.07(br s,2H), 3.65(m,4H), 2.45(m, 4H),2.36(s, 3H) 473 I-178

1-(4-{4-[6-Amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-benzoyl}-piperazin-1-yl)-ethanone 1.67 seeexamples (300 MHz, CDCl₃) δ 7.97(d, J=1.8 Hz,1H), 7.50(m, 6H),7.30(dd, J=2.0 Hz,J=8.3 Hz, 1H), 7.18(d, J=1.8 Hz, 1H),5.22(s, 2H),4.87(br s, 2H), 3.64(m,4H), 3.53(m, 4H), 2.14(s, 3H) 501 I-179

4-[6-Amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide 1.12 seeexamples (300 MHz, CDCl₃) δ 7.98(d, J=1.8 Hz, 1H), 7.81(d,J=8.3 Hz, 2H), 7.55(d,J=8.3 Hz, 2H), 7.46(m, 2H), 7.30(dd, J=2.0 Hz,J=8.3 Hz, 1H), 7.18(d, J=1.8 Hz,1H), 6.09(br d, 1H), 5.22(s, 2H),4.83(br s, 2H), 4.05(m, 1H), 3.06 (m,1H), 2.46(s, 3H), 2.32(m, 1H),2.12(m,1H), 1.83(m, 1H), 1.26(m, 2H),0.88(m, 2H) 486 I-180

4-[6-Amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide 3.8 seeexamples (300 MHz, CDCl₃) δ 7.98(d, J=1.8 Hz,1H), 7.84(d, J=8.3Hz, 2H), 7.56(d,J=8.3 Hz, 2H), 7.46(m, 2H), 7.30(dd,J=2.0 Hz, J=8.3 Hz,1H), 7.20(d,J=1.8 Hz, 1H), 6.90(br t, 1H), 5.22(s, 2H), 4.91(br s, 2H),3.75(m, 4H),3.59(m, 2H), 2.65(m, 2H), 2.55(m, 4H) 502 I-181

4-[6-Amino-5-(2,4-dichloro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide 2 seeexamples (300 MHz, CDCl₃) δ 7.99(d, J=1.7 Hz,1H), 7.87(d, J=8.3Hz, 2H), 7.71(m,1H), 7.55(d, J=8.3 Hz, 2H), 7.47(m, 2H),7.30(dd, J=2.0Hz, J=8.3 Hz, 1H), 7.21(d, J=1.7 Hz, 1H), 5.23(s, 2H), 4.91(br s,2H),3.75(m, 4H), 3.59(m, 2H),2.60(m, 6H), 1.83(m, 2H) 516 I-182

4-[6-Amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzoic acidseeexamples (400 MHz, DMSO-d₆) δ 5.35(s, 2H,CH₂), 5.95(br s, 2H, NH₂),7.40–8.00(multiplets, 10H, aromatic) 388(M+) I-183

{4-[6-Amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 0.75 seeexamples ¹H NMR(300 MHz, CDCl₃) δ 7.96(d, J=1.7 Hz, 1H),7.74(d, J=7.8 Hz, 1H), 7.68(d,J=7.7 Hz, 1H), 7.53(m, 6H), 7.15(d, J=1.7Hz, 1H), 5.35(s, 2H), 4.82(br s, 2H),4.42(m, 1H), 3.50(m, 2H),2.65(m, 4H), 2.2–1.5(m, 10H) 525

I-184

{4-[6-Amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone >20seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.7 Hz,1H), 7.74(d, J=7.8 Hz,1H), 7.68(d, J=7.7 Hz, 1H), 7.53(m, 6H), 7.15(d, J=1.7 Hz, 1H), 5.35(s,2H), 4.82(br s, 2H),4.42(m, 1H), 3.50(m, 2H), 2.65(m, 4H), 2.2–1.5(m,10H) 525 I-185

{4-[6-Amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone 1.39 seeexamples (300 MHz, CDCl₃) δ 7.97(d, J=2.1 Hz,1H), 7.74(d, J=7.8Hz, 1H), 7.88(d, J=7.7 Hz, 1H), 7.51(m, 6H), 7.16(d, J=2.1 Hz, 1H),5.35(s, 2H), 4.88(br s, 2H),3.89(m, 1H), 3.65(m, 2H), 3.45(m, 1H),2.75(m, 1H), 2.31(s,3H), 2.22(s, 3H), 2.11(m, 1H),1.89(m, 1H). 485 I-186

[(3S)-3-Amino-pyrrolidin-1-yl]-{4-[6-amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-methanone 0.79 seeexamples (300 MHz, CDCl₃) δ 7.93(d, J=1.4 Hz,1H), 7.74(d, J=7.7Hz, 1H), 7.67(d, J=7.4 Hz, 1H), 7.55(m, 3H), 7.45(m, 3H),7.15(d, J=1.4Hz, 1H), 5.35(s, 2H),5.01(br s, 2H), 3.65(m, 4H), 2.03(m, 3H), 1.75(m,1H), 0.85(m, 1H) 457 I-187

{4-[6-Amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone 1.01 seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.8 Hz,1H), 7.74(d, J=7.9Hz, 1H), 7.66(m, 1H),7.60(m, 1H), 7.47(m, 5H), 7.14(d, J=1.8 Hz, 1H),5.35(s, 2H), 4.81(br s, 2H),4.60(m, 1H), 3.74(m, 1H),2.96(m,2H), 2.65(m, 2H), 2.22(m,1H), 1.85(m, 2H), 1.55(m, 4H),1.25(m,2H), 0.95(m, 2H) 525 I-188

{4-[6-Amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone 1.64 seeexamples (300 MHz, CDCl₃) δ 7.95(d, J=1.8 Hz,1H), 7.74(d, J=7.7Hz, 1H), 7.68(d, J=7.7 Hz, 1H), 7.60(t, J=7.7 Hz, 1H),7.48(m, 5H),7.14(d, J=1.8 Hz, 1H), 5.35(s, 2H), 4.89(br s, 2H), 3.80(m, 2H), 3.51(m,2H), 2.40(m, 4H), 2.32(s, 3H) 471 I-189

1-(4-{4-[6-Amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzoyl}-piperazin-1-yl)-ethanone 6.7 seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.8 Hz,1H), 7.74(d, J=7.7Hz, 1H), 7.68(d, J=7.7 Hz, 1H), 7.60(t, J=7.7 Hz, 1H),7.48(m, 5H),7.14(d, J=1.8 Hz, 1H), 5.36(s, 2H), 4.87(br s, 2H), 3.64(m, 4H), 3.53(m,4H), 2.14(s, 3H) 499 I-190

4-[6-Amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide 3.8 seeexamples (300 MHz, CDCl₃) δ 7.98(d, J=1.8 Hz,1H), 7.79(d, J=8.3Hz, 2H), 7.74(d, J=7.8 Hz, 1H), 7.67(d, J=7.6 Hz, 1H),7.60(m, 1H),7.52(m, 3H), 7.14(d, J=1.8 Hz, 1H), 5.98(m, 1H), 5.36(s, 2H), 4.85(br s,2H), ), 4.05(m, 1H),2.90(m, 2H), 2.32 (s, 3H), 2.18(m, 2H), 2.01(m, 2H),1.62(m, 2H) 485 I-191

4-[6-Amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide 5.2 seeexamples (300 MHz, CDCl₃) δ 7.98(d, J=1.8 Hz,1H), 7.82(d, J=8.4Hz, 2H), 7.74(d,J=7.8 Hz, 1H), 7.68(d, J=7.7 Hz,1H), 7.60(t, , J=7.7Hz,1H), 7.53(m, 3H), 7.17(d, J=1.8 Hz, 1H),6.83(m, 1H), 5.36(s, 2H),4.89(br s, 2H), 3.74(m, 4H),3.57(m, 2H), 2.62(m, 2H), 2.52(m, 4H) 501I-192

4-[6-Amino-5-(2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide 3.8 seeexamples (300 MHz, CDCl₃) δ 7.98(d, J=1.8 Hz,1H), 7.95(m, 1H),7.86(d, J=8.4 Hz,2H), 7.74(d, J=7.7 Hz, 1H), 7.68(d,J=7.7 Hz, 1H),7.60(t,J=7.7 Hz, 1H), 7.53(m, 3H), 7.17(d, J=1.8 Hz, 1H), 5.36(s, 2H),4.94(br s,2H), 4.94(brs, 2H), 3.75(m,4H), 3.59(m, 2H), 2.59(m,6H),1.83(m, 2H) 515 I-193

4-{6-Amino-5-(4-#tertl-butyl-benzyloxy)-pyridin-3-yl]-benzoic acidseeexamples (400 MHz, DMSO-d₆) δ 1.25(s, 9H,t-butyl), 5.20(s, 2H, CH₂),5.95(br s,2H, NH₂), 7.35–8.00(multiplets, 10H, aromatic) 376(M+) I-194

{4-[6-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 1.89 seeexamples (300 MHz, CDCl₃) δ 7.94(d, J=1.7 Hz, 1H), 7.49(m, 8H),7.21(d,J=1.7 Hz, 1H), 5.11(s, 2H), 4.80(br s,2H), 4.48(m, 1H), 3.48(m,2H),2.62(m, 4H), 2.2–1.5(m, 10H),1.34(s, 9H) 513 I-195

{4-[6-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 3.27 seeexamples (300 MHz, CDCl₃) δ 7.94(d, J=1.7 Hz, 1H), 7.49(m, 8H),7.21(d,J=1.7 Hz, 1H), 5.11(s, 2H), 4.80(br s,2H), 4.48(m, 1H), 3.48(m,2H),2.62(m, 4H), 2.2–1.5(m, 10H),1.34(s, 9H) 513 I-196

{4-[6-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-methanone 4.29 seeexamples (300 MHz, CDCl₃) δ 7.94(d, J=2.1 Hz, 1H), 7.54(m, 4H),7.45(d,J=8.3 Hz, 2H), 7.38(d, J=8.3 Hz, 2H),7.21(d, J=1.7 Hz, 1H),5.11(s,2H), 4.84(br s, 2H), 3.89(m, 1H), 3.64(m, 2H),3.42(m, 1H),2.70(m, 1H), 2.31(s, 3H), 2.22(s,3H), 2.05(m, 1H), 1.89(m,1H),1.34(s, 9H) 473 I-197

{4-[6-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone 3.8 seeexamples (300 MHz, CDCl₃) δ 7.93(d, J=1.7 Hz, 1H), 7.48(m, 4H),7.41(m,4H), 7.21(d, J=1.7 Hz, 1H), 5.11(s,2H), 4.85(br s, 2H), 3.80(m,2H),3.52(m, 2H), 2.41(m, 4H), 2.33(s,3H), 1.34(s, 9H) 459 I-198

1-(4-{4-[6-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-benzoyl}-piperazin-1-yl)-ethanone 3 seeexamples (300 MHz, CDCl₃) δ 7.94(d, J=1.8 Hz, 1H), 7.50(m, 8H),7.21(d,J=1.7 Hz, 1H), 5.11(s, 2H),4.90(br s, 2H), 3.64(m, 4H),3.53(m,4H), 2.14(s, 3H), 1.34(s, 9H) 487 I-199

4-[6-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide 2.92 seeexamples (300 MHz, CDCl₃) δ 7.95(d, J=1.8 Hz, 1H), 7.80(d,J=8.3 Hz,2H), 7.54(d, J=8.3 Hz, 2H),7.44(d, J=7.7 Hz, 2H), 7.38(d,J=7.7Hz, 2H), 7.21(d, J=1.8 Hz,1H), 6.05(m, 1H), 5.11(s, 2H),4.80(br s,2H),4.01(m, 1H), 2.84(m, 2H),2.33(s, 3H), 2.20(m, 2H), 2.10(m, 2H),1.62(m,2H), 1.34(s, 9H) 487 I-200

4-[6-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide 6.88 seeexamples (300 MHz, CDCl₃) δ 7.95(d, J=1.8 Hz, 1H), 7.82(d,J=8.3 Hz,2H), 7.54(d, J=8.3 Hz, 2H),7.44(d, J=8.4 Hz, 2H), 7.38(d,J=8.4Hz, 2H), 7.22(d, J=1.8 Hz,1H), 6.91(t, J=4.6 Hz, 1H), 5.10(s,2H),4.90(br s, 2H), 3.74(m, 4H), 3.57(m, 2H), 2.62(m, 2H), 2.51(m,4H),1.34(s, 9H) 489 I-201

4-[6-Amino-5-(4-tert-butyl-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide 6.3 seeexamples (300 MHz, CDCl₃) δ 8.01(t, J=4.5 Hz, 1H), 7.96(d, J=1.8Hz,1H), 7.86(d, J=8.3 Hz, 2H),7.54(d, J=8.3 Hz, 2H), 7.44(d,J=8.4 Hz,2H), 7.38(d, J=8.4 Hz,2H), 7.24(d, J=1.8 Hz, 1H), 5.12 (s, 2H),4.89(brs, 2H), 3.74(m, 4H), 3.59(m, 2H), 2.55(m, 6H),1.82(m, 2H), 1.34(s, 9H)503 I-202

4-[6-Amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acidseeexamples (400 MHz, DMSO-d₆) δ 5.25(s, 2H,CH₂), 5.80(br s, 2H,NH₂),7.20–8.00(multiplets,9H, aromatic) 374 I-203

{4-[6-Amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 1.48 seeexamples (300 MHz, CDCl₃) δ 7.97(d, J=1.7 Hz,1H), 7.52(m, 6H),7.20(m, 1H), 7.05(m,1H), 5.21(s, 2H), 4.80(br s, 2H), 4.45(m,1H),3.52(m, 2H), 2.76(m, 4H), 2.2–1.5(m, 10H) 509 I-204

{4-[6-Amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 2.5 seeexamples (300 MHz, CDCl₃) δ 7.97(d, J=1.7 Hz,1H), 7.52(m, 6H),7.20(m, 1H), 7.05(m,1H), 5.21(s, 2H), 4.80(br s, 2H), 4.45(m,1H),3.52(m, 2H), 2.76(m, 4H), 2.2–1.5(m, 10H) 509 I-205

{4-[6-Amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone 61 seeexamples (300 MHz, CDCl₃) δ 7.97(s, 1H), 7.52(m,6H), 7.20(m, 1H),7.04(m, 1H), 5.21(s,2H), 4.95(br s, 2H), 3.90(m, 1H), 3.61(m,2H),3.33(m, 1H), 2.75(m, 1H), 2.32(s,3H), 2.23(s, 3H), 2.10(m, 1H),1.89 (m,1H) 469 I-206

{4-(6-Amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone 1.83 seeexamples (300 MHz, CDCl₃) δ 7.97(d, J=1.8 Hz,1H), 7.52(m, 6H),7.20(m, 1H), 7.04(m,1H), 5.21(s, 2H), 4.84(brs, 2H), 3.84(m,4H), 2.15(m,1H), 1.76(m, 2H),1.56(m, 2H) 441 I-207

{4-(6-Amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone 5 seeexamples (300 MHz, CDCl₃) δ 7.96(s, 1H), 7.52(m,6H), 7.20(m, 1H),7.04(m, 1H), 5.21(s,2H), 4.89(br s, 2H), 3.80(m, 2H), 3.65(m, 2H),2.43(m, 4H), 2.33(s, 3H) 456 I-208

1-(4-{4-(6-Amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-benzoyl}-piperazin-1-yl)-ethanone 5.3 seeexamples (300 MHz, CDCl₃) δ 7.96(s, 1H), 7.52(m,6H), 7.20(m,1H), 7.04(m, 1H), 5.21(s,2H), 4.90(br s, 2H), 3.67(m, 4H), 3.53(m, 4H),2.22(s, 3H) 483 I-209

4-[6-Amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide11 seeexamples (300 MHz, CDCl₃) δ 7.99(d, J=1.6 Hz,1H), 7.84(d, J=8.3Hz, 2H), 7.57(d, J=8.3 Hz, 2H), 7.49(dd, J=6.0 Hz, 8.5 Hz,1H), 7.20(m,2H), 7.04(m, 1H), 6.82(m,1H), 5.22(s, 2H), 4.85(br s, 2H),3.74(m, 4H),3.58(m, 2H), 2.63(m, 2H), 2.53(m, 4H) 485 I-210

4-[6-Amino-5-(2-chloro-4-fluoro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide 5.8 seeexamples (300 MHz, CDCl₃) δ 8.06(m, 1H), 7.00(d,J=1.6 Hz, 1H),7.89(d, J=8.3 Hz, 2H),7.55(d, J=8.3 Hz, 2H), 7.49(dd, J=6.0 Hz, 8.5 Hz,1H), 7.20(m, 2H), 7.04(m,1H), 5.22(s, 2H), 4.85(br s, 2H),3.75(m, 4H),3.60(m, 2H), 2.55(m, 6H), 1.83(m, 2H) 499 I-211

4 [6 Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid  0.35 seeexamples (300 MHz, DMSO-d₆) δ 5.21(s, 2H),5.71(s, 2H),7.31–7.46(m, 1H), 7.5–7.62(m, 4H), 7.91–7.94(m, 3H). I-212

{4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone 0.063 seeexamples (300 MHz, CDCl₃) δ 7.97(d, J=1.6 Hz,1H), 7.56(d,J=8.2 Hz, 2H), 7.48(d, J=8.2 Hz, 2H), 7.35(d, J=1.6 Hz, 1H), 7.20(m,1H), 7.06(m, 1H), 5.29(s, 2H), 4.81(br s, 2H), 3.79(m, 2H), 3.54(m,2H),2.44(m, 4H), 2.33(s, 3H) 473 I-213

{4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone 0.049 seeexamples (300 MHz, CDCl₃) δ 7.97(d, J=1.7 Hz, 1H),7.55(d,J=8.2 Hz, 2H), 7.45(d, J=8.2 Hz,2H), 7.35(d, J=1.6 Hz, 1H), 7.20(m,1H),7.06(m, 1H), 5.29 (5. 2H), 4.79(br s, 2H),4.60(m, 1H), 3.85(m, 1H),3.02(m, 2H),2.65(m, 4H), 2.35 (m, 1H),2.05(m, 4H), 1.65(m, 4H). 527I-214

{4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-amino-piperidin-1-yl)-methanone 0.1 seeexamples (400 MHz, DMSO-d₆) δ 7.92(s, 1H), 7.66(m,4H), 7.46(m,4H), 5.89(s, 2H), 5.39(s,2H), 4.19(m, 1H), 3.50(m, 2H), 2.54(m,5H),1.95(m, 2H), 1.83(m, 3H),1.64(m, 4H) MS (ES+)m/z 543(MH+)MS m/z473[M +1] I-215

{4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone 0.1 seeexamples (400 MHz, DMSO-d₆) δ 7.98(s, 1H), 7.58(d, 2H), 7.41(d,2H), 7.31(s, 1H), 7.19(m,1H), 7.06(m, 1H), 5.31(s, 2H), 4.81(m,2H),4.68(m, 1H), 3.69(m, 1H),2.89(m, 2H), 2.69(m, 1H),2.40(m, 1H), 1.74(m,1H), 1.18(d, 6H) 487 I-216

{4-[6-Amino-5-(2-chlora-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 0.1 seeexamples (400 MHz, DMSO-d₆) δ 7.95(d,1H), 7.69(d, 2H),7.58(m,2H), 7.50(d, 2H), 7.40(m, 1H), 5.81(s,2H), 5.29(s, 2H), 4.35(m,1H), 3.5(d, 2H),2.87(d, 2H), 2.71(d, 2H), 1.7–2.0(m, 10H) 527 I-217

{4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone 0.12 seeexamples (400 MHz, DMSO-d₆) δ 7.97(s,1H), 7.60(m, 4H), 7.32(s,1H), 7.18(m,1H), 7.04(m, 1H), 5.31(s, 2H), 4.78(m,2H), 3.90(m, 1H),3.68(m, 2H), 3.41(m,1H), 2.78(m, 1H), 2.31(s, 3H),2.24(s, 3H), 2.08(m,1H),1.84(m, 1H) 487 I-218

{4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3R)-3-amino-pyrrolidin-1-yl]-methanone 0.053 seeexamples (400 MHz, DMSO-d₆) δ 7.84(s, 1H),7.62(m, 5H), 7.35(m,1H), 7.20(m, 1H),5.38(s, 2H), 3.78(m, 3H), 3.55(m, 1H),3.41(m, 1H),2.18(m, 1H), 1.82(m, 1H) 459 I-219

{4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone 0.095 seeexamples 400 MHz, DMSO-d₆) δ 7.84(s, 1H),7.62(m, 5H), 7.35(m,1H), 7.20(m, 1H),5.38(s, 2H), 3.78(m, 3H), 3.55(m, 1H),3.41(m, 1H),2.18(m, 1H),1.82(m, 1H) 459 I-220

4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide 0.11 seeexamples (400 MHz, DMSO-d₆) δ 7.97(s, 1H),7.80(d, 2H), 7.58(d,2H), 7.36(s, 1H),7.18(m, 1H), 7.04(m, 1H), 6.01(d, 1H),5.28(s, 2H),4.78(s, 2H),3.98(m, 1H), 2.85(m, 2H), 2.31(s, 3H),2.18(t, 2H), 2.10(m,2H),1.65(m, 2H) 487 I-221

4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(2-pyrrolidin-1-yl)-ethyl)-benzamide 0.18 seeexamples (400 MHz, DMSO-d₆) δ 7.98(s, 1H),7.89(d, 2H), 7.56(d,2H), 7.45(m, 1H),7.31(s, 1H), 7.17(m, 1H), 7.01(m, 1H),5.28(s, 2H),4.85(s, 2H),3.65(m, 2H), 2.89(t, 2H), 2.76(m, 4H),1.89(m, 4H) 487 I-222

4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(3-pyrrolidin-1-yl)-propyl)-benzamide 0.19 seeexamples (400 MHz, DMSO-d₆) δ 8.72(m, 1H),7.95(m, 3H), 7.57(d,2H), 7.35(s, 1H),7.18(m, 1H), 7.02(m, 1H), 5.31(s, 2H),4.79(s, 2H),3.68(m, 2H),2.89(m, 6H), 1.97(m, 6H) 501 I-223

4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl)-ethyl)-benzamide 0.165 seeexamples (400 MHz, DMSO-d₆) δ 7.97(s, 1H),7.82(d, 2H), 7.62(d,2H), 7.36(s, 1H),7.18(m, 1H), 7.05(m, 1H), 6.81(m, 1H),5.28(s, 2H),4.79(s, 2H),3.78(m, 4H), 3.58(m, 2H), 2.83(t, 2H),2.51(m, 4H) 503 I-224

4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide 0.28 seeexamples (400 MHz, DMSO-d₆) δ 8.04(m, 1H),7.96(s, 1H), 7.89(d,2H), 7.58(d, 2H),7.38(s, 1H), 7.18(m, 1H), 7.06(m, 1H),7.29(s, 2H),4.81(s, 2H),3.76(m, 4H), 3.61(m, 2H), 2.59(t, 2H),2.54(m, 4H), 1.79(m,2H) 517 I-225

3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoicacid 3.7/0.6 seeexamples (300 MHz, CDCl₃) δ 8.15(s, 1H), 7.92(s, 1H),7.84(d, J=7.4 Hz, 1H),7.60(m, 2H), 7.55(s, 1H), 7.40(m, 2H),5.75(s, 2H),5.31(br s, 2H) 391 I-226

{3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone 0.068 seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.7 Hz,1H), 7.58(dd,J=1.1 Hz, 6.8 Hz, 1H), 7.46(m, 1H), 7.35(m, 3H), 7.20(m, 1H), 7.06(m,1H), 5.27(s, 2H), 4.81(br s, 2H),3.83(m, 2H), 3.50(m, 2H), 2.49(m, 2H),2.39(m, 2H), 3.33(s, 3H) 473 I-227

{3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone 0.05 seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.8 Hz,1H), 7.57(dd,J=1.2 Hz, 8.0 Hz, 1H), 7.45(t, J=7.6 Hz, 1H), 7.34(m, 3H), 7.20(m,1H),7.06(m, 1H), 5.27(s, 2H), 4.77(br s,2H), 4.60(m, 1H), 3.80(m, 1H),3.02(m,2H), 2.60(m, 2H), 2.30 (m,1H), 1.95(m, 2H), 1.85(m, 4H),1.65(m,4H) 527 I-228

{3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-amino-piperidin-1-yl)-methanone 0.23 seeexamples (300 MHz, CD-₃OD) δ 8.01(s, 1H), 7.89(s, 1H), 7.75(m,2H), 7.59(s, 1H), 7.48(t,1H), 7.31(m, 1H), 7.18(m, 1H), 5.38(s,2H),4.01(m, 1H), 3.09(m, 2H),2.68(t, 2H), 1.97(m, 2H), 1.58(m,2H) 473 I-229

{3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone 0.066/ 0.18 seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.7 Hz,1H),7.56(m, 1H), 7.47(t, J=7.6 Hz, 1H),7.36(m, 3H), 7.20(m, 1H), 7.06(m,1H),5.27(s, 2H), 4.82(br s, 2H), 4.68(m, 1H),3.65(m, 1H), 3.90(m, 2H),2.702.40 (m, 1H), 1.97(m, 1H),1.15(d, 3H), 0.99(d, 3H) 487 I-230

{3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone 0.19 seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.7 Hz,1H), 7.66(s, 1H),7.57(d, J=6.8 Hz,1H), 7.45(m, 2H), 7.36(d, J=1.7 Hz, 1H),7.20(m, 1H),7.06(m, 1H), 5.27(s, 2H),4.78(br s, 2H), 4.42(m, 1H),1H), 3.45(m, 2H),2.68(m, 4H), 2.2–1.5(m, 10H) 527 I-231

{3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone 0.128 seeexamples (300 MHz, CDCl₃) δ 7.96(s, 1H), 7.68(d,J=7.4 Hz, 1H),7.59(m, 1H), 7.44(m,2H), 7.36(s, 1H), 7.20(m, 1H), 7.06(m,1H), 5.27(s,2H), 4.80(br s,2H), 3.90(m, 1H), 3.61(m, 2H), 3.41(m,1H), 2.77 (m, 1H),2.32(s, 3H), 2.22(s, 3H), 2.10(m,1H), 1.82(m, 1H) 487 I-232

{3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3R)-3-amino-pyrrolidin-1-yl]-methanone 0.12 seeexamples (300 MHz, CD₃OD) δ 7.86(s, 1H), 7.75(m,2H), 7.58(m,3H), 7.38(m, 1H), 7.22(m,1H), 5.38(s, 2H), 4.00–3.56(m, 5H, 2.40(m, 1H),2.12 (m,1H) 459 I-233

{3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-[(3S)-amino-pyrrolidin-1-yl]-methyanone 0.12 seeexamples (300 MHz, CD₃OD) δ 7.86(s, 1H), 7.75(m,2H), 7.58(m,3H), 7.38(m, 1H), 7.22(m,1H), 5.38(s, 2H), 4.00–3.56(m, 5H), 2.40(m,1H), 2.12 (m,1H). 459 I-234

3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamide 0.23 seeexamples (300 MHz, CDCl₃) δ 7.96(d, J=1.7 Hz, 1H),7.94(s, 1H),7.64(m, 2H), 7.47(t, J=7.7 Hz, 1H), 7.37(d, J=1.7 Hz, 1H),7.20(m, 1H),7.06(m, 1H), 6.25(m, 1H),5.27(s, 2H), 4.81(br s, 2H), 3.99(m, 1H),2.84(m, 2H), 2.30(s,3H), 2.16(m, 2H), 2.04(m, 2H), 1.64(m, 2H) 487 I-235

3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide 0.26 seeexamples (300 MHz, CDCl₃) δ 8.02(s, 1H), 7.96(d,J=1.7 Hz, 1H),7.72(d, J=7.7 Hz, 1H),7.64(d, J=7.8 Hz, 1H), 7.47(t, J=7.7 Hz,1H),7.40(d, J=1.7 Hz, 1H),7.20(m, 2H), 7.06(m, 1H), 5.27(s, 2H),4.83(br s,2H), 3.61(m, 2H),2.77 (m, 2H), 2.62(m,4H), 1.81(m, 4H) 487 I-236

3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(3-pyrrolidin-1-yl-propyl)-benzamide 0.28 seeexamples (300 MHz, CDCl₃) δ 8.78(m, 1H), 8.04(d,J=1.6 Hz, 1H),7.98(d, J=1.6 Hz, 1H),7.68(d, J=7.7 Hz, 1H), 7.63(d, J=7.9 Hz,1H),7.45(t, J=7.7 Hz, 1H),7.43(d, J=1.6 Hz, 1H), 7.20(m, 1H),7.06(m, 1H),5.29(s, 2H),4.77 (br s, 2H), 3.61(m, 2H),2.77(m, 2H), 2.66(m, 4H),1.87(m, 2H), 1.80(m, 4H) 501 I-237

3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide 0.35 seeexamples (300 MHz, CDCl₃) δ 7.99(t, J=1.5 Hz,1H), 7.97(d, J=1.8Hz, 1H), 7.66(m, 2H),7.49(t, J=7.7 Hz, 1H), 7.38(d, J=1.8 Hz,1H),7.20(m, 1H), 7.06(m, 2H),5.27(s, 2H), 4.85(br s, 2H), 3.72(m,4H),3.59(m, 2H), 2.63(m, 2H), 2.52(m, 4H) 503 I-238

3-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-N-(3-morpholin-4-yl-propyl)-benzamide 0.35 seeexamples (300 MHz, CDCl₃) δ 8.02(m, 2H), 7.97(d,J=1.8 Hz, 1H),7.68(d, J=7.8 Hz, 1H),7.65(d, J=8.3 Hz, 1H), 7.48(t, J=7.7 Hz,1H),7.38(d, J=1.8 Hz, 1H), 7.19(m, 1H),7.06(m, 1H), 5.27(s, 2H), 4.81(br s,2H),3.66(m, 4H), 3.59(m, 2H), 2.55(m, 2H), 2.49(m, 4H), 1.81(m, 2H) 517I-239

N-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzamide 0.1 seeexamples (300 MHz, CDCl₃) δ 8.00(s, 1H),7.86(s, 1H), 7.67(dd,2H), 7.56(t, 1H),7.48(s, 1H), 7.21(m, 1H), 7.08(m, 1H),6.02(br s, 2H),5.39(s, 2H), 3.75(m,4H), 3.60(m, 2H), 2.79(m, 2H), 2.60(m, 4H), 2.11(s,3H) 544 I-240

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylamine 0.1 seeexamples (400 MHz, DMSO-d₆) δ 7.88(s, 1H),7.62(d, 2H), 7.56(m,1H), 7.51(s, 1H),7.40(m, 1H), 7.23(d, 2H), 5.70(s,2H), 5.28(s, 2H),3.76(t, 2H), 3.49(t, 2H), 2.41(t, 2H) 466 I-241

3-(2,6-Dichloro-benzyloxy)-4-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylamine 0.067 seeexamples 464 I-242

5-[4-(1,1-Dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-3-(2-fluoro-6-trifluoromethyl-benzyloxy)-pyridin-2-ylamine 0.14 seeexamples 482 I-243

2-Diethylamino-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amine 0.043 seeexamples (300 MHz, CDCl₃) δ 7.92(d, J=1.8 Hz,1H), 7.48(d,J=8.4 Hz, 2H), 7.31(d, J=1.8 Hz, 1H), 7.24(m, 3H), 7.20(m, 1H),7.07(m,1H), 5.28(s, 2H), 4.70(br s,2H), 3.22(t, J=6.1 Hz, 2H), 3.04(t, J=6.1Hz, 2H), 2.65(q, J=7.1 Hz, 4H), 1.10(t, J=7.1 Hz, 6H) 525 I-244

2-Cydopropylamino-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 0.081 seeexamples (300 MHz, CDCl₃) δ 7.92(d, J=1.8 Hz,1H), 7.48(d,J=8.4 Hz, 2H), 7.31(d, J=1.8 Hz, 1H), 7.24(m, 3H),7.20(m, 1H), 7.07(m,1H), 5.28(s,2H), 4.75(br s, 2H), 3.25(s, 4H),2.17(m, 1H),0.9(m, 1H),0.50(m, 2H), 0.40(m, 2H) 509 I-245

2-Pyrrolidin-1-yl-ethanesulfonic acid{4-]6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 0.082 seeexamples (300 MHz, CDCl₃) δ 7.92(d, J=1.8 Hz,1H), 7.48(d,J=8.5 Hz, 2H), 7.31(d, J=1.8 Hz, 1H), 7.24(m, 3H),7.20(m, 1H), 7.07(m,1H), 5.28(s,2H), 4.72(br s, 2H), 3.27(m, 2H),3.06(m, 2H), 2.59 (m, 4H),1.86(m, 4H) 523 I-246

2-(4-Hydoxy-piperidin-1-yl)-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 0.135 seeexamples (300 MHz, CDCl₃) δ 7.92(d, J=1.8 Hz,1H), 7.48(d,J=8.5 Hz, 2H), 7.32(m, 2H), 7.24(m, 2H), 7.20(m, 1H),7.07(m, 1H),5.28(s, 2H), 4.74 (br s, 2H), 3.81(m, 1H), 3.31(t,2H), 2.98(t,2H) 2.85(m,2H), 2.32(m, 2H), 1.98(m, 2H),1.68(m, 3H) 553 I-247

2-Morpholin-4-yl-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 0.31 seeexamples (300 MHz, DMSO-d₆) δ 9.80(br s, 1H),7.89(d, J=1.6 Hz,1H), 7.59(m, 3H), 7.52 (d, J=1.6 Hz, 1H), 7.26(d, J=8.6 Hz, 2H),5.72(brs, 2H), 5.28(s, 2H), 3.49(m, 4H), 3.28(t, 2H), 2.69(t,2H), 2.31(m, 4H)539 I-248

2-Pipendin-1-yl-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 0.114 seeexamples (300 MHz, CDCl₃) δ 7.93(d, J=1.8 Hz,1H), 7.48(d,J=8.5 Hz, 2H), 7.30(m, 2H), 7.24(m, 2H), 7.20(m, 1H), 7.07(m, 1H),5.28(s, 2H), 4.70(br s,2H), 3.25(t, 2H), 2.92(t, 2H), 2.52(m, 4H),1.85(m, 4H), 1.63(m, 2H) 537 I-249

2-Dimethylamino-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 0.098 seeexamples (300 MHz, CDCl₃) δ 7.92(d, J=1.8 Hz,1H), 7.48(d,J=8.5 Hz, 2H), 7.30(m, 2H), 7.24(m, 2H), 7.20(m, 1H), 7.07(m, 1H),5.28(s, 2H), 4.71(br s,2H), 3.20(t, 2H), 2.88(t, 2H), 2.32(s, 6H) 497I-250

2-(4-Acetyl-piperazin-1-yl)-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 0.42 seeexamples (300 MHz, CDCl₃) δ 7.92(d, J=1.8 Hz,1H), 7.48(d, J=8.5Hz, 2H), 7.30(m, 2H), 7.24(m, 1H), 7.20(m, 1H), 7.07(m, 2H), 5.28(s,2H), 4.80(br s,2H), 3.65(m, 2H), 3.48(m, 2H), 3.32(t, 2H), 2.94(t,2H), 2.50(m, 2H), 2.46(m, 2H), 2.10(s, 3H) 580 I-251

2-(Cyclopropylmethyl-amino)-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 0.075 seeexamples (300 MHz, CDCl₃) δ 7.94(s, 1H), 7.48(m,2H), 7.31(m,3H), 7.21(m, 1H),7.18(m, 1H), 5.28(s, 2H), 4.75(s, 2H),3.23(m, 4H),2.58(m, 2H), 1.00(m, 1H),0.58(m, 2H), 0.18(m, 2H) 523 I-252

2-[(3R)-3-Hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 0.125 seeexamples (300 MHz, CDCl₃) δ 7.92(s, 1H), 7.43(m,2H), 7.31(m,3H), 7.19(m, 1H),7.05(m, 1H), 5.28(s, 2H), 4.75(s, 2H),4.45(m, 1H),3.29(m, 2H), 3.10(m, 3H),2.88(m, 1H), 2.61(m, 1H), 2.30(m, 2H), 1.89(m,2H) 539 I-253

2-[(2S)-2-Hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 0.097 seeexamples (300 MHz, CDCl₃) δ 7.89(s, 1H), 7.45(m,2H), 7.30(m,3H), 7.21(m, 1H),7.08(m, 1H), 5.31(s, 2H), 4.78(s, 2H),3.55(m, 2H),3.36(t, 1H), 3.11(m, 2H),2.69(m, 2H), 2.21(m, 1H), 1.89(m, 6H) 553 I-254

2-[4-(2-Hydroxy-acetyl)-piperazin-1-yl]-ethanesulfonic acid{4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin3-yl]-phenyl}-amide 0.18 seeexamples (300 MHz, DMSO-d₆) δ 9.81(s, 1H), 7.89(s, 1H), 7.58(d,2H), 7.50(s, 1H),7.39(m, 2H), 7.24(d, 2H), 5.75(s, 2H),5.28(s, 2H),4.54(t, 1H), 4.01(d,2H), 3.29(m, 6H), 2.79(t, 2H),2.36(m, 4H) 596 I-255

2-(4-Acetyl-piperazin-1-yl)-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 0.68 seeexamples (300 MHz, CDCl₃) δ 2.02(s, 3H), 2.30(m, 4H), 2.95(m,4H), 3.35(m, 4H),3.55(m, 2H), 5.30(d, 2H), 5.42(s, 2H),7.05(m, 1H),7.20(m, 1H), 7.35(m,5H), 8.00(d, 1H), 10.17(s, 1H) 580 I-256

2-Pyrrolidin-1-yl-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 0.23 seeexamples (300 MHz, CDCl₃) δ 1.60–1.80(m, 4H),2.40–2.55(m, 4H),3.02(t, J=6.6 Hz, 2H),3.29(t, J=6.6 Hz, 2H), 5.08(s, 2H),5.29(d, J=1.3Hz, 2H), 6.95–7.05(m, 1H), 7.10–7.20 (m, 1H),7.25–7.45(m, 5H),7.97(d,J=1.7 Hz, 1H) 524 I-257

2-Morpholin-4-yl-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 1.64 seeexamples (300 MHz, CDCl₃) δ 2.42(t, J=4.6 Hz,4H), 2.90(t, J=6.9Hz, 2H), 3.31(t, J=6.9 Hz, 2H), 3.62(t, J=4.6 Hz, 4H),5.24(s, 2H),5.30(d, J=1.3 Hz, 2H),6.95–7.05(m, 1H), 7.10–7.20(m,1H),7.30–7.45(m, 5H),7.99(d, J=1.6 Hz, 1H), 9.38(s, 1H) 540 I-258

2-Diethylamino-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}amide 1.67 seeexamples (300 MHz, CDCl₃) δ 1.00(t, 6H), 2.52(q,4H), 3.02(t,2H), 3.25(t, 2H), 5.19(s, 2H),5.29(d, 2H), 7.05(m, 1H), 7.20(m,1H),7.35(m, 5H), 7.98(d, 1H) 526 I-259

2-Dimethylamino-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 1.5 seeexamples (300 MHz, CDCl₃) δ 2.24(s, 6H), 2.85(t,2H), 3.24(t,2H), 5.11(s, 2H), 5.29(d, 2H),7.07(m, 1H), 7.15(m, 1H), 7.35(m,5H),7.98(d, 1H) 498 I-260

2-Pipendin-1-yl-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 1.63 seeexamples (300 MHz, CDCl₃) δ 1.30–1.60(m, 6H),2.30–2.45(m 4H),2.89(t, J=6.7 Hz, 2H),3.28(t, J=6.7 Hz, 2H), 5.13(s, 2H),5.29(d, J=1.4Hz, 2H), 6.95–7.05(m, 1H), 7.15–7.45(m, 6H), 7.98(d,J=1.6 Hz, 1H) 538I-261

2-[(3R)-3-Hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 1.7 seeexamples (300 MHz, CDCl₃) δ 1.60–1.8(m, 4H),2.05–2.15(m, 1H),2.55–2.75(m, 2H),2.95–3.15(m, 2H), 3.25–3.55(m, 3H),3.82(dd, J=3.0. 11.2Hz, 1H), 4.97(s, 2H), 5.28(d, J=1.6 Hz, 2H),6.98–7.08 (m, 1H),7.10–7.20(m, 1H), 7.25–7.45(m, 5H),7.98(d, J=1.8 Hz, 1H) 554 I-262

2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 1.5 seeexamples (300 MHz, DMSO-d₆) δ 1.15–1.30(m,2H), 1.45–1.55(m, 2H),1.90–2.02(m,2H), 2.50–2.70(m, 4H), 4.49(brs, 1H),5.28(s, 2H), 5.82(s,2H), 7.05–7.10(m, 1H), 7.20–7.40(m, 5H), 7.45–7.60(m, 1H),7.83(d, J=1.6Hz, 1H) 554 I-263

2-[4-(2-Hydroxy-acetyl)-piperazin-1-yl]-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 1.14 seeexamples (300 MHz, CDCl₃) δ 2.36(m, 4H), 2.92(t,2H), 3.14(m,2H), 3.32(t, 2H), 3.54(m,2H), 3.60(br s, 1H), 4.07(s, 2H),5.30(s, 2H),5.40(br s, 2H),7.06(m, 1H), 7.24(m, 2H), 7.34(m,2H), 7.44(m,2H), 7.99(d, J=1.6 Hz, 1H), 9.88(br s,1H) 596 I-264

2-[(3R)-3-Hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 1.097 seeexamples (300 MHz, CDCl₃) δ 1.65(m, 1H), 2.08(m,1H), 2.22(m,1H), 2.46(m, 1H),2.76(m, 1H), 2.87(m, 1H), 3.02(m, 2H),3.32(m, 2H),4.28(m, 1H), 5.28(br s, 2H)5.29(s, 2H), 7.06(m, 1H), 7.24(m,2H), 7.44(m,5H), 8.00(d, J=1.7 Hz, 1H) 539 I-265

2-(Cyclopropylmethyl-amino)-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 1 seeexamples (300 MHz, CDCl₃) δ 0.02(m, 2H), 0.39(m,2H), 0.84(m, 1H),2.40(d, 2H),3.14(t, 2H), 3.32(t, 2H), 5.28(s, 2H),5.38(br s, 2H),7.06(m, 1H),7.24(m, 2H), 7.44(m, 5H), 8.00(d,J=1.7 Hz, 1H) 523 I-266

2-Cyclopropylamino-ethanesulfonic acid{3-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-amide 0.9 seeexamples (300 MHz, CDCl₃) δ 0.28(m, 2H), 0.37(m,2H), 2.06(m,1H), 3.15–3.40(m, 4H), 5.30(d, 2H), 5.39(s,2H), 7.07(m, 1H), 7.19(m,1H), 7.30–7.55(m, 5H), 8.01(d, 1H) 509 I-267

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(2-dimethylaminomethyl-phenyl)-pyridin-2-ylamine;compoundwith trifluoro-acetic acid seeexamples 404 I-268

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(3-pyrrolidin-1-yl-phenyl)-pyridin-2-ylamine;compoundwith trifluoro-acetic acid  4 seeexamples (400 MHz, DMSO-d₆) δ 1.94(t,4H), 3.31(t, 4H), 5.44(s, 2H), 6.56(d, 1H),6.74(s, 1H), 6.88(d, 1H),7.24(t, 1H),7.43(m, 1H), 7.58(m, 3H), 7.83(m, 2H) 416 I-269

N-{4-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide;compoundwith trifluoro-acetic acid seeexamples (400 MHz, DMSO-d₆) δ 2.99(s, 3H),5.35(s, 2H), 6.72(br s, 2H), 7.27(d,2H), 7.42(m, 1H), 7.59(m,1H),7.65(d, 2H), 7.73(s, 1H), 7.84(s, 1H),9.79(s, 1H) 440 I-270

5-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophene-2-carboxylicacid seeexamples 397 I-271

{5-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophen-2-yl}-(4-methyl-piperazin-1-yl)-methanoneseeexamples (300 MHz, CDCl₃) δ 8.00(d, J=1.8 Hz,1H), 7.30(d, J=1.8 Hz,1H),7.25(d, J=1.5 Hz, 1H), 7.20(m,1H), 7.10(d, J=3.8 Hz, 1H), 7.07(m,1H), 5.27(d, J=1.7 Hz, 2H),4.82(br s, 2H), 3.81(m, 4H),2.47(m, 4H),2.34(s, 3H) 479 I-272

{5-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophen-2-yl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanoneseeexamples (300 MHz, CDCl₃) δ 8.02(d, J=1.8 Hz,1H), 7.52(m, 1H),7.32(d, J=1.8 Hz,1H), 7.21(m, 1H), 7.14(d, J=3.9 Hz,1H), 7.07(m, 1H),5.27(d, J=1.5 Hz,2H), 4.80(br s, 2H), 4.50(m, 1H),3.81(m, 2H), 2.74(m,4H), 2.25–1.82(m, 10H). 533 I-273

5-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophene-2-carboxylicacid (1-methyl-piperidin-4-yl)-amide seeexamples (300 MHz, CDCl₃) δ8.02(d, J=1.8 Hz,1H), 7.42(d, J=3.9 Hz, 1H), 7.29(d,J=1.8 Hz, 1H),7.21(m, 1H), 7.15(d,J=3.9 Hz, 1H), 7.07(m, 1H), 5.89(br d,1H), 5.29(d,J=1.5 Hz, 2H),4.82(br s, 2H), 4.05(m, 1H),3.05(m, 2H), 2.50(s, 3H),2.40(m, 2H), 1.85(m, 2H), 1.62(m, 2H) 493 I-274

{5-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophen-2-yl}-(3,5-dimethyl-piperazin-1-yl)-methanoneseeexamples (300 MHz, CDCl₃) δ 8.00(d, J=1.8 Hz,1H), 7.30(d, J=1.8 Hz,1H), 7.24(d,J=3.8 Hz, 1H), 7.21(m, 1H), 7.10(d,J=3.8 Hz, 1H), 7.07(m,1H), 5.28(d,J=1.5 Hz, 2H), 4.82(br s, 2H),4.38(m, 2H), 2.98 (m, 2H),2.65(m, 2H), 1.68(br s, 1H), 1.11(d,J=6.2 Hz, 6H) 493 I-275

5-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophene-2-carboxylicacid(2-pyrrolidin-1-yl-ethyl)-amide seeexamples (300 MHz, CDCl₃) δ 8.00(d,J=1.8 Hz,1H), 7.82(br m, 1H), 7.66(d, J=3.9 Hz,1H), 7.29(d, J=1.8 Hz,1H), 7.21(m,1H), 7.11(d, J=3.9 Hz, 1H), 7.07(m, 1H), 5.26(d, J=1.5 Hz,2H),4.81(br s, 2H), 3.71(m, 2H), 3.02(m, 2H), 2.95(m, 2H), 2.01(m,4H),1.97(m, 2H), 1.11(d, J=6.2 Hz, 6H) 493 I-276

{5-[6-Amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-thiophen-2-yl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanoneseeexamples (300 MHz, CDCl₃) δ 8.00(d, J=1.8 Hz,1H), 7.29(d, J=1.8 Hz,1H), 7.24(d, J=3.8 Hz, 1H), 7.20(m, 1H), 7.09(d, J=3.8 Hz, 1H),7.07(m,1H), 5.27(d, J=1.5 Hz, 2H), 4.80(br s,2H), 4.43(m, 2H), 3.10(m,2H),2.63 (m, 4H), 2.34(m, 1H), 1.99(m, 2H), 1.83(m, 4H),1.63(m, 2H). 533I-277

4-[6-Amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzoicacid seeexamples 407 I-278

{4-[6-Amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanoneseeexamples (300 MHz, CDCl₃) δ 7.97(d, J=1.8 Hz,1H), 7.61–7.42(m, 6H),7.21(d,J=8.7 Hz, 1H), 7.12 (d, J=1.8 Hz, 1H), 5.33(s, 2H), 4.81(brs,2H), 4.62(m, 1H), 3.84(m, 1H),2.98(m, 2H), 2.65(m, 4H), 2.32(m, 1H),1.97(m, 2H), 1.84(m,4H), 1.60(m, 2H) 543 I-279

4-[6-Amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-N-(1-methyl-piperidin-4-yl)-benzamideseeexamples (300 MHz, CDCl₃) δ 7.99(d, J=1.8 Hz,1H), 7.80(d, J=8.3 Hz,2H),7.55(m, 1H), 7.52(d, J=8.3 Hz, 2H),7.44(d, .J=7.8 Hz, 1H), 7.22(t,J=8.7 Hz, 1H), 7.12 (d, J=1.8 Hz, 1H), 5.99(br d, 1H), 5.34(s, 2H),4.83(br s, 2H),4.04(m, 1H), 2.87(m, 2H),2.34(s, 3H), 2.20(m, 2H),2.05(m,2H), 1.63(m, 2H) 503 I-280

{4-[-Amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanoneseeexamples (300 MHz, CDCl₃) δ 7.98(s, 1H), 7.61–7.43(m, 6H), 7.22(t,J=8.7 Hz, 1H),7.13(d, J=1.6 Hz, 1H), 5.33(s, 2H),4.82(br s, 2H), 4.65(m,1H), 3.65(m, 1H), 2.90(m, 2H), 2.68(m, 1H),2.42(m, 1H), 1.60(m, 1H),1.12(d, 3H), 1.00(d, 3H) 503 I-281

{4-[6-Amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3-dimethylamino-pyrrolidin-1-yl)-methanoneseeexamples (300 MHz, CDCl₃) δ 7.98(d, J=2.4 Hz,1H), 7.61–7.43(m, 6H),7.21(t, J=8.8 Hz,1H), 7.14(d, J=2.4 Hz, 1H), 5.33(s,2H), 4.87(br s, 2H),3.89(m, 1H),3.65(m, 2H), 3.42(m, 1H), 2.70(m, 1H), 2.32(s, 3H), 2.23(s,3H),2.14 (m, 1H), 1.82(m, 1H) 503 I-282

{4-[6-Amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanoneseeexamples (300 MHz, CDCl₃) δ 7.98(d,J=1.4 Hz, 1H), 7.58–7.43(m,6H),7.20(t, J=8.8 Hz, 1H), 7.13(d, J=1.4 Hz, 1H), 5.34(s, 2H), 4.81(br s,2H), 4.46(m, 1H), 3.50(m, 2H),2.77(m, 4H), 2.30–1.50(m, 10H) 543 I-283

4-[6-Amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-#N1-(2-morpholin-4-yl-ethyl)-benzamideseeexamples (300 MHz, CDCl₃) δ 8.00(d,J=1.2 Hz, 1H), 7.83(d, J=8.2 Hz,2H), 7.56(m, 1H), 7.55(d, J=8.2 Hz, 2H), 7.45(d, 1H), 7.20(t, J=8.8 Hz,1H), 7.13(d, J=1.4 Hz, 1H), 6.76(m, 1H), 5.34(s, 2H), 4.85(br s,2H),3.74(m, 4H), 3.56(m, 2H),2.62(m, 2H), 2.52(m, 4H) 519 I-284

{4-[6-Amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanoneseeexamples (300 MHz, CDCl₃) δ 7.97(d,J=1.8 Hz, 1H), 7.58–7.43(m,6H),7.20(t, J=8.8 Hz, 1H), 7.12(d, J=1.8 Hz, 1H), 5.34(s, 2H),4.93(br s,2H), 3.80(m, 2H), 3.56(m, 2H), 2.44(m, 4H), 2.33(s, 3H) 489 I-285

N-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-benzamideseeexamples (300 MHz, CDCl₃) δ 8.00(d,J=1.2 Hz, 1H), 7.82(d, J=8.2 Hz,2H),7.58(m, 1H), 7.55(d, J=8.2 Hz, 2H), 7.44(d, J=7.8 Hz, 1H), 7.22(t,J=8.8 Hz, 1H),7.14(d, J=1.4 Hz, 1H), 6.72(m,1H), 5.34(s, 2H), 4.85(br s,2H), 3.65(m,2H), 3.60(m, 2H), 3.50(m,2H), 2.65(m, 2H), 2.51(m,4H),2.10(s, 3H) 560 I-286

2-Piperidin-1-yl-ethanesulfonic acid(4-{6-amino-5-[1-(2-cloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.18 seeexamples (300 MHz, CDCl₃) δ 7.84(d, 1H),7.26(d, 2H), 7.20(d,2H), 7.06(m,3H), 7.59(s, 1H), 4.86(s, 2H), 3.25(m,2H), 2.89(m, 2H),2.49(m, 4H), 1.83(d,3H), 1.62(m, 4H), 1.48(m, 2H) 551 I-287

2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.14 seeexamples (300 MHz, CDCl₃) δ 7.84(d, 1H),7.26(d, 2H), 7.20(d,2H), 7.06(m,3H), 7.59(s, 1H), 4.86(s, 2H), 3.76(m,1H), 3.25(m, 2H),2.89(m, 2H),2.78(m, 2H), 2.26(m, 2H), 1.83(m,5H), 1.62(m, 2H) 567 I-288

2-Dimiethylamino-ethanesulfonicacid(4-}6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.15 seeexamples (300 MHz, CDCl₃) δ 7.84(d, 1H),7.26(d, 2H), 7.20(d,2H), 7.06(m,3H), 7.59(s, 1H), 4.86(s, 2H), 3.21(m,2H), 2.88(m, 2H),2.30(s, 6H),2.26(m, 2H), 1.82(d, 3H) 511 I-289

2-Cyclopropylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.16 seeexamples (300 MHz, CDCl₃) δ 7.89(s, 1H),7.38(d, 2H), 7.26(d,2H), 7.18(m,3H), 5.95(m, 1H), 4.89(s, 2H), 3.22(m,4H), 2.14(m, 1H),1.85(d, 3H),0.50(m, 2H), 0.38(m, 2H) 523 I-290

4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid seeexamples 422 I-291

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone 0.063 seeexamples (300 MHz, CDCl₃) δ 7.84(d, 1H),7.52(d, 2H), 7.31(d,2H), 7.08(m, 3H),6.13(m, 1H), 4.86(s, 2H), 4.30(m, 1H),3.40(m, 2H),2.60(m, 4H), 1.82(d, 3H),1.70–2.0(m, 10H) 557 I-292

4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide 0.069 seeexamples (300 MHz, CDCl₃) δ 7.84(d, 1H),7.78(d, 2H), 7.35(d,2H), 7.31(m, 3H),6.16(tert, 1H), 5.90(d, 1H), 4.86(s,2H), 4.05(m, 1H),2.85(d, 1H), 2.35(s, 3H), 2.05(d, 1H), 2.25(t, 1H),1.82(d, 3H), 1.60 (m,1H), 1.29(m,2H), 0.86(m, 2H) 559 I-293

(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-[(3R)-3-amino-pyrrolidin-1-yl)]-methanone 0.051 seeexamples (300 MHz, CDCl₃) δ 7.84(d, 1H),7.51(s, 1H), 7.38(m,3H), 7.30(m, 1H),7.15(m, 1H), 6.97(s, 1H), 6.15(m, 1H),4.94(s, 2H),3.45–3.89(m, 4H), 3.20(m, 1H), 2.25(m, 1H), 2.15(m, 1H),1.82(d, 3H),1.34(m, 2H) 489 I-294

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone 0.062 seeexamples (300 MHz, CDCl₃) δ 7.84(d, 1H),7.70(m, 1H), 7.45(m,1H), 7.30(s, 2H),7.08(t, 1H), 6.92(d, 2H), 6.13(m, 1H),4.86(s, 2H),4.30(t, 1H), 2.80(m, 4H), 1.82(d, 3H), 1.80(m, 4H),1.35(m, 4H), 0.89(m,4H) 559 I-295

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone 0.079 seeexamples (300 MHz, CDCl₃) δ 7.89(s, 1H),7.71(d, 2H), 7.49(d,2H), 7.40(s, 1H),7.35(m, 1H), 7.08(m, 1H), 6.17(m, 1H),4.98(s, 2H),4.28(t, 2H), 3.68(m, 4H), 2.38(m, 2H), 2.31(s, 3H),1.88(d, 3H) 503 I-296

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-methyl-piperazin-1-yl)-methanone 0.054 seeexamples I-297

2-Cyclopropylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.164 seeexamples (300 MHz, CDCl₃) δ 7.79(s, 1H),7.30(m, 3H), 7.24(m,3H), 7.08(t, 1H),6.95(s, 1H), 6.09(m, 1H), 4.89(s, 2H),3.21(m, 4H), 2.12(m, 1H), 1.84(d, 3H), 0.87(m, 1H), 0.50(m, 2H),0.36(m, 2H) 539 I-298

2-Dimethylamino-ethanesulfonicacid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.059 seeexamples (300 MHz, CDCl₃) δ 7.81(s, 1H),7.26(m, 6H), 7.04(t,1H), 6.94(s, 1H),6.12 (m, 1H), 4.95(s, 2H), 3.21(t, 2H),2.85(t, 2H),2.31(s, 6H), 1.85(d, 3H) 527 I-299

2-[(3R)-3-Hydroxy-pyrrolidin-1-yl)]-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.062 seeexamples (300 MHz, CDCl₃) δ 7.84(d, 1H),7.30(m, 5H), 7.10(t,1H), 6.89(s, 1H),6.10(tert, 1H), 4.86(s,2H), 4.40(s, 1H), 3.21(m, 2H),2.88(m, 3H), 2.67(d, 1H), 2.46(m,1H), 2.20(m, 2H), 2.05(s, 1H),1.85(d,3H), 1.25(s, 1H) 570 I-300

N-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzamide 0.059 4 as inExampleI-291 (300 MHz, CDCl3) δ 7.85(s, 1H),7.79(d, 2H),7.42(d, 2H), 7.30(dd,1H), 7.07(t, 1H), 7.02(d,1H), 6.81 (bm, 1H),6.13(q, 1H),5.42(s, 2H), 3.80(m, 2H), 3.62(m, 2H), 3.53(m, 2H),2.68 (m,2H), 2.52(m, 4H), 2.10(s, 3H),1.87(d, 3H). 575[M + 1] I-301

4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide 0.064 4 as inExampleI-291 (300 MHz, CDCl3) δ 8.71 (bm, 1H),7.92(m, 3H),7.42(d, 2H), 7.31(dd,1H), 7.06(t, 1H), 7.01(s,1H), 6.12 (q, 1H), 4.97(s,2H),3.65(m, 2H), 3.00(m, 6H), 2.00(m, 6H), 1.87(d, 3H). 533[M + 1] I-302

4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide 0.071 4 as inExampleI-291) (300 MHz, CDCl3) δ 7.90(d, 1H),7.79(d, 2H),7.44(d, 2H), 7.31(dd,1H), 7.06(t, 1H), 7.01(d,1H), 6.83 (bm, 1H), 6.12(q, 1H),5.05(s, 2H), 3.74(m, 4H), 3.58(m, 2H), 2.63(m, 2H),(m, 4H),1.87(d, 3H). 533[M + 1] I-303

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone 0.059 4 as inExampleI-291 (300 MHz, CD3OD) δ 7.76(s, 1H),7.54(m, 1H),7.42(m, 4H), 7.24(t,1H), 7.04(s, 1H), 6.22(q,1H), 4.82(s, 2H), 3.76(m,1H), 3.68(m,2H), 3.52(m, 1H), 2.28(m, 1H),1.92(m, 3H), 1.75(m, 1H),1.42(m, 1H). 491[M + 1] I-304

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone 0.072 4 as inExampleI-291 (300 MHz, CD3OD) δ 7.76(s, 1H),7.54(m, 1H),7.42(m, 4H), 7.24(t,1H), 7.04(s, 1H), 6.22(q,1H), 4.82(s, 2H), 3.76(m,1H), 3.68(m,2H), 3.52(m, 1H), 2.28(m, 1H),1.92(m, 3H), 1.75(m, 1H),1.42(m, 1H). 491[M + 1] I-305

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-amino-piperidin-1-yl)-methanone 0.18 4 as inExampleI-291 504[M + 1] I-306

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-hydroxy-pyrrolidin-1-yl)-methanone 0.024 4 as inExampleI-291 (300 MHz, CD3OD) δ 7.78(d, 1H),7.47(m, 3H),7.37(m, 3H), 6.92(d,1H), 6.07(q, 1H), 5.88(s,2H), 4.82(dd, 1H), 4.15(d,1H), 3.53(m, 2H), 3.42(m, 1H), 3.15(m, 1H),2.43(m, 1H), 1.85(m, 1H),1.75(d, 3H). 491[M + 1] I-307

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone 0.022 4 as inExampleI-291 (300 MHz, CD3OD) δ 7.80(d, 1H),7.47(m, 3H),7.37(m, 3H), 6.92(d,1H), 6.07(q, 1H), 5.89(s,2H), 4.82(dd, 1H), 4.15(d,1H), 3.53(m, 2H), 3.42(m, 1H), 3.15(m, 1H),2.43(m, 1H), 1.85(m, 1H),1.75(d, 3H). 491[M + 1] I-308

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone 0.033 4 as inExampleI-291 (300 MHz, CD3OD) δ 7.80(d, 1H),7.47(m, 3H),7.37(m, 3H), 6.92(d,1H), 6.07(q, 1H), 5.89(s,2H), 4.70(m, 1H),4.05(m,1H), 3.5(m, 2H), 3.32(m, 1H),2.43(m, 1H), 1.85(m, 3H),1.75(d,3H), 1.15(m, 1H). 505[M + 1] I-309

4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-diethylamino-ethyl)-benzamide 0.04 4 as inExampleI-291 (300 MHz, CDCl3) δ 9.55 (bm, 1H), 8.80(t, 1H),7.95(s, 1H), 7.58(d, 2H),7.55(m, 3H), 7.45(t, 1H), 7.09(d,1H), 6.23(q,1H), 3.60(q, 2H), 3.22(m, 5H, 3.09(m, 1H), 1.85(d, 3H),1.22(dd, 6).516[M + 1] I-310

4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide 0.12 4 as inExampleI-291 (300 MHz, CDCl3) δ 8.25 (bm, 1H), 7.90(d, 1H),7.82(s, 2H), 7.34(d, 2H),7.25(m, 1H), 7.04(t, 1H), 6.96(s,1H), 6.09(q,1H), 4.97(s, 2H), 3.82(m, 2H), 3.15(m, 6H), 2.00(m, 4H),1.85(d, 3H).518[M + 1] I-311

3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid 3 as inExample211 420[M − 1] I-312

(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone 0.062 4 (300 MHz, CDCl3) δ 7.86(s, 1H), 7.41(m, 3H), 7.30(m, 3H),7.07(t, 1H),6.99(s, 1H), 6.12 (q, 1H), 4.99(s,2H), 3.89(m, 2H), 3.50(m,2H),2.54(m, 2H), 2.40(m, 2H), 2.35(s, 3H),1.87(d, 3H). 503[M + 1] I-313

3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)benzamide 0.069 4 as inExampleI-312 (300 MHz, CDCl3) δ 7.89(s, 1H), 7.76(s, 1H),7.67(d, 1H), 7.49(d, 1H),7.42(t, 1H), 7.31(dd, 1H), 7.05(t, 1H), 7.01(s,1H), 6.28 (bd, 1H),6.12 (q, 1H), 4.99(s, 2H), 4.08(m, 1H),3.04(m, 2H),2.42(s, 3H), 2.32(m,2H), 2.10(m, 2H), 1.87(d, 3H),1.80(m, 2H). 517[M +1] I-314

(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone 0.06 4 as inExampleI-312 (300 MHz, CDCl3) δ 7.87(s, 1H),7.40(m, 4H),7.29(dd, 1H), 7.05(t,1H), 7.00(s, 1H), 6.12 (q, 1H), 4.92(s, 2H),3.50(m, 2H), 3.74(m, 4H),1.86(d, 3H), 1.57–2.18(m, 11H), 559[M + 1]I-315

N-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzamide 0.069 4 as inExampleI-312 (300 MHz, CDCl3) δ 7.88(s, 1H), 7.83(s, 1H),7.65(d, 1H), 7.46(m, 2H),7.32(dd, 1H), 7.06(t, 1H), 7.03(s, 1H), 6.95(bt, 1H), 6.12 (q, 1H),5.08(s, 2H), 3.66(m, 4H), 3.50(m, 2H), 2.73(m,2H), 2.52(m,4H), 2.09(s, 3H), 1.87(d, 3H). 576[M + 1] I-316

(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone 0.048 4 as inExampleI-312 (300 MHz, CDCl3) δ 7.87(s, 1H),7.38(m, 4H),7.28(m, 1H), 7.06(t,1H), 6.98(s, 1H), 6.12 (q,1H), 5.05(s, 2H), 3.82(m,2H), 3.72(m, 2H), 2.10(m, 1H), 1.86(d, 3H),1.84(m, 2H). 491[M + 1] I-317

3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-morpholin-4-yl-propyl)-benzamide 0.059 4 as inExampleI-312 (300 MHz, CDCl3) δ 7.91(s, 1H),7.87(s, 1H),7.85(d, 1H), 7.50(m,2H), 7.31(dd, 1H), 7.04(m, 2H),6.13(q, 1H), 4.93(s,2H), 3.64(m,6H), 2.50(m, 6H), 1.87(d, 3H),1.81(m, 2H), 1.81(m, 2H).549[M + 1] I-318

(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone 0.13 4 as inExampleI-312 (300 MHz, CDCl3) δ 7.87(s,1H), 7.40(m, 4H),7.29(dd, 1H),7.05(t, 1H), 7.00(s, 1H), 6.12 (q,1H), 4.92(s, 2H), 3.50(m,2H), 3.74(m,4H), 1.86(d, 3H), 1.57–2.18(m, 11H). 558[M + 1] I-319

3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide 0.1 4 as inExampleI-312 (300 MHz, CDCl3) δ 7.86(s, 1H), 7.82(s,1H),7.73(d, 1H), 7.46(m, 4H), 7.22(t, 1H), 7.04(s, 1H), 6.95 (bt,1H),6.22(q, 1H), 4.82(s, 2H), 360(m, 2H), 2.82(m, 2H), 2.70(m, 4H),1.87 (d,3H), 1.82(m, 2H). 518[M + 1] I-320

3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide 0.13 4 as inExampleI-312 (300 MHz, CDCl3) δ 8.66 (bt, 1H), 7.90(s, 1H),7.85(s, 1H), 7.61(d, 1H),7.42(m, 2H), 7.31(dd, 1H), 7.05(m,2H), 6.14(q,1H), 4.88(s, 2H),3.65(m, 2H), 2.71(m, 2H), 2.56(m,4H), 1.87(d, 3H),1.80 (m, 2H),1.71(m, 4H). 531[M + 1] I-321

3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide 0.18 4 as inExampleI-312 (300 MHz, CDCl3) δ 7.90(s, 1H), 7.84(s, 1H),7.66(d, 1H), 7.46(m, 2H),7.32(dd, 1H), 7.05(m, 2H), 6.88 (bt,1H),6.14(q, 1H), 5.04(s, 2H),3.82(m, 4H), 3.66(m, 2H), 2.72(t,2H), 2.60(m,4H), 1.88 (d, 3H). 535[M + 1] I-322

(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone 0.071 4 as inExampleI-312 (300 MHz, CDCl3) δ 7.86(s, 1H), 7.41(m, 3H),7.30(m, 3H), 7.07(t, 1H),6.99(s, 1H), 6.12 (q, 1H), 4.95(s,2H), 4.70(m,1H), 3.82(m, 1H),(m, 1H), 2.98(m, 1H), 2.65(m, 4H),2.28(m, 1H), 1.02(m,1H), 1.81(m, 5H), 1.55(m, 2H). 559[M + 1] I-323

2-Diethylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.08 9 (300 MHz, CDCl3) δ 7.83(s, 1H), 7.32(m, 4H), 7.21(d, 2H),7.06(t, 1H),6.96(s, 1H), 5.96(q, 1H), 4.81(s,2H), 3.22(m, 2H), 3.02(m,2H),2.62(m, 4H), 1.84(d, 3H), 1.08(t, 6H), 571[M + 1] I-324

2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy[-pyridin-3-yl}-phenyl)-amide 0.059 9 as inExampleI-297 (300 MHz, CDCl3) δ 7.81(s, 1H), 7.31(m, 3H),7.25(m, 3H), 7.07(t, 1H),6.96(s, 1H), 6.11(q, 1H), 4.95(s,2H), 3.76(m,1H), 3.25(t, 2H),2.92(t, 2H), 2.79(m, 2H), 2.25(m, 2H), 1.93(m, 2H),1.86(d, 3H),1.62(m, 2H). 583[M + 1] I-325

2-Piperidin-1-yl-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy[-pyridin-3-yl}-phenyl)-amide 0.089 9 as inExampleI-297 (300 MHz, CDCl3) δ 7.84(s, 1H), 7.32(m, 4H),7.21(d, 2H), 7.06(dd, 1H),6.96(s, 1H), 6.11(q, 1H), 4.88(s,2H), 3.24(t,2H), 2.89(t, 2H),2.48(m, 4H), 1.86(d, 3H), 1.62(m,4H), 1.49(m, 2H),558[M + 1] I-326

2-(Cyclopropylmethyl-amino)-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.075 9 as inExampleI-297 (300 MHz, CDCl3) δ 7.83(s, 1H), 7.28(m, 6H),7.06(dd, 1H), 6.96(s, 1H),6.11(q, 1H), 4.91(s, 2H), 3.22(m,4H), 2.50(d,2H), 1.86(d, 3H),0.84(m, 2H), 0.52(m, 2H), 0.15(m,1H). 517[M + 1] I-327

2-((R)-3-Hydroxy-pyrrolidin-1-yl)-ethanesulfonicacid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy[-pyridin-3-yl}-phenyl)-amide 0.093 9 as inExampleI-286 (300 MHz, CDCl3) δ 7.83(s, 1H), 7.32(m, 5H),7.05(m, 3H), 5.95(q, 1H),4.84(s, 2H), 4.43(m, 1H), 3.25(m,2H), 3.02(m,3H), 2.84(m, 1H),2.53(m, 1H), 2.30(m, 1H), 2.22(m,1H), 1.84(d,3H), 1.81(m, 1H). 553[M + 1] I-328

2-Cyclopropylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.16 9 as inExampleI-286 (300 MHz, CDCl3) δ 7.89(s, 1H), 7.38(d, 2H),7.24(m, 2H), 7.18(m, 3H),5.95(q, 1H), 4.89(s, 2H), 3.22(m,4H), 2.14(m,1H), 1.85(d, 3H),0.50(m, 2H), 0.38(m, 2H). 523[M + 1] I-329

2-Diethylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.095 9 as inExampleI-286 (300 MHz, CDCl3) δ 7.84(s, 1H), 7.34(d, 2H),7.23(m, 3H), 7.02(m, 3H),5.96(q, 1H), 4.81(s, 2H), 3.22(m,2H), 3.02(m,2H), 2.62(m, 4H),1.84(d, 3H), 1.08(t, 6H). 539[M + 1] I-330

4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid 3 as inExample211 405[M + 1] I-331

4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide 0.13 4 (300 MHz, CDCl3) δ 7.91(s, 1H), 7.80(d, 2H), 7.46(d, 2H),7.05(m, 3H),6.87(m, 1H), 5.97(q, 1H), 4.97(s,2H), 3.75(m, 4H), 3.58(m,2H),2.60(m, 6H), 1.84(m, 3H). 517[M + 1] I-332

4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide 0.079 4 as inExampleI-331 (300 MHz, CDCl3) δ 7.90(s, 1H), 7.78(d, 2H),7.45(d, 2H), 7.05(m, 4H),5.98(q, 1H), 4.90(s, 2H), 4.00(m,1H), 2.88(m,2H), 2.32(s, 3H),2.18(m, 2H), 2.08(m, 2H), 1.84(d, 3H), 1.57(m, 2H).501[M + 1] I-333

(4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone 0.067 4 as inExampleI-331 (300 MHz, CDCl3) δ 7.90(s, 1H),7.54(m, 2H),7.42(d, 2H), 7.05(m,3H), 5.98(q, 1H), 4.86(s,2H), 3.50(m, 2H), 3.74(m,4H),1.84(d, 3H), 1.57–2.18(m, 11H) 541[M + 1] I-334

(4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone 0.089 4 as inExampleI-331 (300 MHz, CDCl3) δ 7.68(m, 5H),7.25(m, 3H),6.27(m, 1H), 4.88(s,2H), 3.75(m, 5H), 3.31(m,2H), 2.44(m, 18), 2.17(m,1H),1.93(m, 3H). 473[M + 1] I-335

(4-{6Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone 0.09 4 as inExampleI-331 (300 MHz, CDCl3) δ 7.90(s, 1H),7.42(m, 4H),7.05(m, 3H), 5.97(q,1H), 4.86(s, 2H), 4.62(m,1H), 3.65(m, 1H), 2.88(m,2H),2.68(m, 1H), 2.41(m, 1H), 1.84(d, 3H), 1.64(m, 1H), 1.05(m, 6H).501[M + 1] I-336

4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide 0.09 4 as inExampleI-331 (300 MHz, CDCl3) δ 9.00(s, 1H),7.92(s, 1H),7.83(d, 2H), 7.42(d,2H), 7.06(m, 2H), 7.01(m,1H), 5.96(q, 1H), 4.89(s,2H),3.60(m, 2H), 2.75(m, 2H), 2.62(m,4H), 1.85(m, 7H). 515[M + 1] I-337

(4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone 0.09 4 as inExampleI-331 (300 MHz, CDCl3) δ 7.90(s,1H), 7.53(m, 2H),7.43(d, 2H),7.05(m, 3H), 5.98(q, 1H), 4.88(s,2H), 4.45(m, 1H), 3.58(m,2H),3.00(m, 4H), 1.84(d, 3H), 1.70–2.18(m, 10H) 541[M + 1] I-338

(4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone 0.077 4 as inExampleI-331 (300 MHz, CDCl3) δ 7.90(s, 1H),7.44(m, 4H),7.07(m, 3H), 5.95(q, 1H), 4.87(s, 2H), 3.60(m, 4H),2.43(m, 4H), 2.33(s,3H), 1.84(d, 3H). 487[M + 1] I-399

(4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone 0.062 4 as inExampleI-331 (300 MHz, CDCl3) δ 7.90(s, 1H),7.42(m, 4H),7.02(m, 3H), 6.00(q, 1H), 4.87(s, 2H), 4.64(m, 1H),3.85(m, 1H), 2.99(m,2H), 2.67(m, 4H),2.38(m, 1H), 1.90(m, 9H), 1.62(m, 2H). 541[M + 1] I-340

4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide 0.086 4 as inExampleI-331 (300 MHz, CDCl3) δ 7.91(s, 1H),7.86(d, 2H),7.45(d, 2H), 7.10(m, 3H), 7.01(m, 1H), 5.98(q, 1H),4.90(s, 2H), 3.60(m,2H), 2.80(m, 2H),2.68(m, 4H), 1.85(m, 7H). 501[M + 1] I-341

(4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone 0.075 4 as inExampleI-331 (300 MHz, CDCl3) δ 7.76(s, 1H),7.67(m, 2H),7.59(d, 2H), 7.42(s, 1H), 7.32(m, 1H), 7.20(m, 1H),6.27(m, 1H), 4.86(s,2H), 3.75(m, 5H),3.31(m, 2H), 2.44(m, 1H), 2.14(m, 1H), 1.95(m, 3H).473[M + 1] I-342

3-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid as inExample211 405[M + 1] I-343

3-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone 0.16 4 (300 MHz, CDCl3) δ 7.88(s, 1H),7.43(m, 2H), 7.30(m, 2H), 7.10(m,2H), 6.95(m, 1H), 5.97(q, 1H),4.87(s, 2H), 4.65(m, 1H), 3.60(m,1H),2.72(m, 3H), 2.41(m, 1H), 2.01(s, 1H), 1.84(d, 3H), 1.17 (m, 3H),0.98(m,3H). 501[M + 1] I-344

(3-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone 0.12 4 as inExample343 (300 MHz, CDCl3) δ 7.65(m, 5H),7.42(s, 1H),7.32(m, 1H), 7.20(m, 1H), 6.27(m, 1H), 4.85(s, 2H),3.75(m, 5H), 3.31(m,2H), 2.44(m,1H), 2.16(m, 1H), 1.93(m, 3H). 473[M + 1] I-345

3-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide 0.2 4 as inExample343 (300 MHz, CDCl3) δ 7.90(s, 1H),7.78(s, 1H),7.67(d, 1H), 7.45(m, 2H), 7.00(m, 3H), 6.15 (bd,1H), 5.98(q, 1H),4.08(m, 1H), 2.97(m, 2H), 2.38(s, 3H), 2.27(m, 2H),2.10(m, 2H), 1.84(d,3H), 1.74(m, 2H). 501[M + 1] I-346

(3-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone 0.19 4 as inExample343 (300 MHz, CDCl3) δ 7.88(s, 1H),7.42(m, 3H),7.30(m, 2H), 7.09(m, 2H), 7.00(m, 1H), 5.95(q,1H), 4.87(s, 2H), 3.83(m,2H), 3.47(m, 2H), 2.51(m, 2H), 2.33(m, 5H),1.84(d, 3H). 487[M + 1] I-347

3-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide 0.21 4 as inExample343 (300 MHz, CDCl3) δ 8.69(s, 1H),7.91(m, 2H),7.65(d, 1H), 7.42(m, 2H), 7.00(m, 3H), 5.99(q,1H), 4.85(s, 2H), 3.60(m,2H), 2.76(m, 2H), 2.63(m, 4H), 1.84(d, 3H),1.77(m, 6H). 515[M + 1] I-348

3-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide 0.2 4 as inExample343 (300 MHz, CDCl3) δ 7.91(s, 1H),7.86(s, 1H),7.70(d, 1H), 7.50(m, 2H), 7.00(m, 4H), 5.99(q,1H), 4.86(s, 2H), 3.60(m,2H), 2.78(m, 2H), 2.63(m, 4H), 1.85(m, 7H). 501[M + 1] I-349

(3-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone 0.13 4 as inExample343 (300 MHz, CDCl3) δ 7.70(m, 5H),7.42(s, 1H),7.28(m, 1H), 7.20(m, 1H), 6.27(m, 1H), 4.85(s,2H), 3.75(m, 5H), 3.31(m,2H), 2.66(m, 1H), 2.44(m, 1H), 1.93(m, 3H). 473[M + 1] I-350

3-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide 0.39 4 as inExample343 (300 MHz, CDCl3) δ 7.91(s, 1H),7.84(s, 1H),7.65(d, 1H), 7.46(m, 2H), 7.05(m, 3H), 6.83(bs, 1H), 5.97(q, 1H),4.91(s, 2H),3.74(m, 4H), 3.58(m, 2H), 2.63(m,2H), 2.52(m, 4H), 1.84(m,3H). 517[M + 1] I-351

3-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone 0.23 4 as inExample343 (300 MHz, CDCl3) δ 7.88(s, 1H),7.45(m, 4H),7.05(m, 3H), 5.98(q, 1H), 4.86(s, 2H), 4.45(m, 1H), 3.64(m, 1H), 3.44(m,1H),2.64(m, 4H) 1.83(d, 3H), 1.70–2.18(m, 10H) 541[M + 1] I-352

3-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone 0.15 4 as inExample343 (300 MHz, CDCl3) δ 7.88(s, 1H),7.45(m, 4H),7.09(m, 3H), 5.98(q, 1H), 4.86(s, 2H), 4.45(m, 1H), 3.45(m, 2H), 2.75(m,4H),1.84(d, 3H), 1.70–2.18(m, 10H) 541[M + 1] I-353

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine 0.23 3 as inExampleI-2 I-354

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine 0.22 3 as inExampleI-2 I-355

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-2-ylamine 0.068 3 as inExampleI-2 (400 MHz, DMSO-d6): d 7.74(d, J=2.0 Hz,1H),7.53(m, 1H), 7.44(m, 2H), 7.32(d,J=9.0 Hz, 2H), 7.00(d, J=8.6 Hz, 2H),6.88(d, J=1.6 Hz, 1H), 6.11(m, 1H), 5.79(s,2H), 4.30(m, 2H), 3.5(m,6H),1.90(m, 4H), 1.807(d, J=6.7 Hz, 3H). 491[M + 1] I-356

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-{4-[2-1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-pyridin-2-ylamine 0.079 3 as inExampleI-2 (400 MHz, DMSO-d6): d 7.73(s, 1H), 7.54(m, 1H),7.44(m, 2H), 7.284(d, J=8.2 Hz,2H), 6.95(d, J=8.6 Hz, 2H), 6.88(s,1H,pyridine-H), 6.10(m, 1H), 5.78(s, 2H),4.7(m, 1H), 3.3(m, 2H),3.1(m, 2H),2.77(s, 3H), 2.3(m, 6H), 1.81(d, J=6.2 Hz,3H). 504[M + 1]I-357

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine 0.13 3 as inExampleI-2 (400 MHz, DMSO-d6): d 7.72(d, 1H), 7.53(m, 1H),7.44(m, 1H), 7.33(m, 2H), 7.03(m,3H), 6.23(q, 1H), 4.35(m, 2H),3.95(m,1H), 3.0–3.8(m, 9H), 1.851(d, 3H). 506[M + 1] I-358

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine 0.22 3 as inExampleI-2 (400 MHz, DMSO-d6): d 7.82(d, 1H), 7.53(q, 1H),7.46(t, 1H), 7.33(t, 1H), 7.03(m,3H), 6.95(dd, 1H), 6.24(q,1H), 4.38(m,2H), 3.95(m, 2H),3.75(m, 2H), 3.61(m, 2H), 3.5(m,2H), 3.25(m, 2H),1.851(d, 3H). 506[M + 1] I-359

1-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-3-morpholin-4-yl-propan-2-ol 0.045 3 (400 MHz, DMSO-d6): d 7.73(d, J=1.6 Hz,1H), 7.56(m, 1H),7.44(t, J=8.6 Hz,1H), 7.28(d, J=6.7 Hz, 2H),6.94(d, J=8.6 Hz, 2H),6.88(d, J=2.0 Hz, 1H), 6.11(m,1H), 5.75(s, 2H), 4.88(d, J=2.0 Hz, 1H),3.96(m,3H), 3.57 (t, J=4.3 Hz,4H), 2.42 [m, 6H), 1.81(d,J=6.7 Hz, 3H).536[M + 1] I-360

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-diethylamino-ethoxy)-phenyl]-pyridin-2-ylamine 0.033 3 as inExampleI-2 (400 MHz, DMSO-d6): d 7.73(d, J=1.6 Hz,1H),7.56(m, 1H), 7.44(t, J=8.6 Hz,1H), 7.28(d, J=8.6 Hz, 2H),6.92(d, J=8.6Hz, 2H), 6.88(d, J=1.6 Hz, 1H), 6.11(m,1H), 5.75(s, 2H), 4.02(t, J=6.2Hz,2H), 2.756(m, 2H), 2.55 (m, 4H),1.81(d, J=6.7 Hz, 3H),0.99(t, J=7.0Hz, 6H). 494[M + 1] I-361

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(1-methyl-piperidin-3-ylmethoxy)-phenyl]-pyridin-2-ylamine 0.043 3 as inExampleI-2 (400 MHz, DMSO-d6): d 7.73(d, J=2.0 Hz,1H),7.53(m, 1H), 7.44(t, J=8.6 Hz, 1H),7.27(d, J=6.7 Hz, 2H), 6.92(d, J=8.6Hz,2H), 6.87(d, J=1.6 Hz, 1H), 6.10(m, 1H),5.75(s, 2H), 3.831(m, 2H),2.81(m,1H), 2.62(s, 1H), 2.153(s,3H), 1.95(m, 3H), 1.81(d,J=6.7 Hz, 3H),1.72(m, 4H). 504[M + 1] I-362

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-diisopropylamino)-ethoxy)-phenyl]-pyridin-2-ylamine 0.052 3 as inExampleI-2 (400 MHz, DMSO-d6): d 7.73(d, J=2.0 Hz,1H),7.53(m, 1H), 7.44(t, J=8.6 Hz, 1H),7.27(m, 2H), 6.91(m, 2H), 6.88(d,J=2.0 Hz, 1H), 6.11(m, 1H), 5.74(s, 2H), 3.88(t, J=6.7 Hz, 2H),3.02(m,2H), 2.76(t, 3 =6.7 Hz,2H), 1.81(d, J= 6.7 Hz, 3H),0.986(m, 12H).520[M + 1] I-363

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(1-methyl-piperidin-4-yloxy)-phenyl]-pyridin-2-ylamine 0.052 3 (400 MHz, DMSO-d6): d 7.66(d, J=1.6 Hz,1H), 7.49(m, 1H),7.377(t, J=8.2 Hz,1H), 7.20(m, 2H), 6.87(m, 2H),6.81(d, J=1.6 Hz, 1H),6.04(m, 1H), 5.68(s, 2H), 4.30(m, 1H),2.55(m, 2H), 2.12 (m, 5H), 1.84(m,2H),1.74(d, J=6.7 Hz, 3H),1.57(m, 2H). 490[M + 1] I-364

N-(4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanesulfonamide 0.1 3 as inExampleI-135 454[M + 1]

I-365

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-[4-(1,1-dioxo-1lambda*6*-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylamine 0.14 3 as inExampleI-240 478[M + 1] I-366

N-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanesulfonamide 0.076 3 as inExampleI-135 (300 MHz, CDCl3) δ 9.75(s, 1H), 7.88(d,1H),7.55(q, 1H), 7.45(t, 1H),7.35(d, 2H), 7.18(d, 2H), 6.9(d,1H), 6.10(q,1H), 5.85(s, 2H),2.99(s, 3H), 1.80(d, 3H). 470[M + 1] I-367

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-phenyl-pyridin-2-ylamine 0.5 3 (300 MHz, CDCl3) δ 7.80(d, 1H), 7.55(q,1H), 7.45(t, 1H), 7.35(dd,4H),7.25(m, 1H), 6.95(d, 1H), 6.12(q, 1H), 5.85(s, 2H), 1.80(d, 3H).377[M + 1] I-368

N-(4-{6-Amino-5-[(R)-1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanesulfonamide 0.066 3 as inExampleI-135 (300 MHz, CDCl3) δ 9.80(s, 1H), 7.70(d,1H),7.43(m, 3H), 7.30(ddd, 1H),7.25(d, 1H), 7.18(m, 2H), 6.10(q,1H), 2.95(s,3H), 1.75(d, 3H). 454[M + 1] I-369

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-thiophen-3-yl-pyridin-2-ylamine 0.055 3 383[M + 1] I-370

5-Benzo[b]thiophen-2-yl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine 1.95 3 433[M + 1] I-371

4-Methyl-piperazine-1-carboxylic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.057 10 (300 MHz, CDCl3) δ 7.71(s, 1H), 7.40(d,2H), 7.32–7.23(m, 3H),7.06(t, 1H), 6.99(s, 1H), 6.77(bs,1H), 6.11(q, 1H), 5.62(s, 2H), 3.60(m,4H), 2.57(m, 4H), 2.40(s,3H), 1.87(d, 3H). 518[M + 1] I-372

1-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea 0.21 10 as inExampleI-371 532[M + 1] I-373

1-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-hydroxy-ethyl)-urea 0.064 10 as inExampleI-371 (300 MHZ, CDCl3) δ 7.68(s, 2H), 7.45(m,2H),7.36(d, 2H), 7.25(m, 2H),6.95(s, 2H), 6.55(q, 1H), 4.88(s,2H), 3.83(t,2H), 3.31(m, 3H), 1.87(d, 3H). 479[M + 1] I-374

1-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea 0.062 10 as inExampleI-371 (300 MHz, CDCl3) δ 7.88(s, 1H), 7.55(m,3H),7.35(d, 2H), 7.23(m, 3H),6.95(s, 1H), 6.55(q, 1H), 4.86(s,2H), 3.71(t,2H), 3.31(m, 6H), 2.51(m, 4H), 1.88(d, 3H).   548.2[M + 1] I-375

(R)-3-Amino-pyrrolidine-1-carboxylix acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.053 10 as inExampleI-371 (300 MHz, CDCl3) δ 7.65(m, 4H), 7.31(m,3H),7.19(m, 2H), 6.37(m, 1H),4.87(s, 2H), 3.95(m, 1H), 3.80(m,1H), 3.60(m,2H), 3.31(m, 2H), 2.45(m, 1H), 2.18(m, 1H), 1.95(d, 3H).   503.8[M + 1]I-376

(S)-3-Amino-pyrrolidine-1-carboxylic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.052 10 as inExampleI-371 (300 MHz, CDCl3) δ 7.85(m, 4H), 7.31(m,3H),7.19(m, 2H), 6.37(m, 1H),4.87(s, 2H), 3.95(m, 1H), 3.80(m,1H), 3.60(m,2H), 3.31(m, 2H), 2.45(m, 1H), 2.18(m, 1H), 1.95(d, 3H).   504.1[M + 1]I-377

1-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(1-methyl-pipendin-4-yl)-urea 0.04 10 as inExampleI-371 534[M + 1] I-378

1-(4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(1-methyl-pipendin-4-yl)-urea 0.038 10 as inExampleI-371 518[M + 1] I-379

(R)-3-Amino-pyrrolidine-1-carboxylic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.069 10 as inExampleI-371 488[M + 1] I-380

(S)-3-Amino-pyrrolidine-1-carboxylic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy}-pyridin-3-yl}-phenyl)-amide 0.075 10 as inExampleI-371 488[M + 1] I-381

1-(4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-hydroxy-ethyl)-urea 0.11 10 as inExampleI-371 (300 MHz, CDCl3) δ 7.69(d, 2H), 7.37(d,2H),7.25(d, 2H), 7.15(m, 2H),7.09(d, 2H), 6.00(q, 1H), 4.86(s,2H), 3.63(t,2H), 3.32(m, 3H), 1.83(d, 3H). 463[M + 1] I-382

4-Methyl-piperazine-1-carboxylic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amine 0.082 10 as inExampleI-371 (300 MHz, CDCl3) δ 7.78(s, 1H), 7.41(d,2H),7.29(d, 2H), 7.09(s, 1H),7.05(m, 1H), 6.95(m, 1H), 6.56(bs, 1H), 6.00(q,1H), 5.25(s, 2H),3.58(m, 4H), 2.53(m, 4H), 2.38(s, 3H), 1.84(d, 3H).502[M + 1] I-383

1-(4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea 0.11 10 as inExampleI-371 516[M + 1] I-384

1-(4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea 0.13 10 as inExampleI-371 (300 MHz, CDCl3) δ 7.83(d, 1H), 7.29(m,5H),7.00(m, 4H), 5.94(q, 1H),4.87(bs, 2H), 3.67(m, 4H), 3.38(m, 2H), 2.52(m,4H), 1.86(d, 3H).   533.7[M + 1] I-385

(R)-2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylicacid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide 0.13 10 as inExampleI-371 (300 MHz, CDCl3) δ 7.93(s, 1H), 7.67(d,2H),7.27(d, 2H), 6.95(m, 4H),6.70(q, 1H), 4.84(s, 2H), 3.85(m, 1H), 3.75(m,1H), 3.40(m, 1H),2.90(m, 4H), 2.65(m, 4H), 2.10(m, 3H), 1.85(d, 3H),1.9–1.7(m, 3H).   555.8[M + 1] I-386

3-(6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid3 as inExampleI-211 403[M + 1] I-387

(3-{6-Aminno-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone 0.16 4 (300 MHz, CDCl3) δ 7.86(s, 1H), 7.39(m,4H), 7.31(d, 2H), 7.15(t,1H),7.02(s, 1H), 6.15(m, 1H), 4.93(s,2H), 4.65(m, 1H), 3.56(m,1H),2.95(m, 1H), 2.79(m, 1H), 2.71(m,1H), 2.44(m, 1H), 1.84 (d,3H),1.95(m, 1H), 1.25(d, 3H),1.17(d, 3H). 501[M + 1] I-388

(3-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone 0.1 4 as inExampleI-387 (300 MHz, CDCl3) δ 7.85(s, 1H), 7.39(m,4H),7.32(d, 2H), 7.15(t, 1H),7.02(s, 1H), 6.15(m, 1H), 4.90(s,2H), 4.65(m,1H), 3.65(m, 1H),3.05(m, 2H), 2.80(m, 1H), 2.65(m,4H), 2.30(m, 1H),2.05 (m, 1H),1.86(d, 3H), 1.81(m, 3H), 1.52(m, 4H). 539[M + 1] I-389

3-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide 0.13 4 as inExampleI-387 (300 MHz, CDCl3) δ 7.88(s, 1H), 7.82(s,1H),7.69(d, 1H), 7.45(m, 3H),7.32(d, 2H), 7.15(t, 1H), 7.06(s,1H), 6.99(bm,1H), 6.16(q, 1H),4.93(s, 2H), 3.61(m, 2H), 2.78(m,2H), 2.63(m, 4H),1.87(d, 3H),1.82 (m, 4H). 501[M + 1] I-390

3-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide 0.12 4 as inExampleI-387 (300 MHz, CDCl3) δ 7.89(s, 1H), 7.82(s,1H),7.65(d, 1H), 7.48(m, 3H),7.32(d, 2H), 7.15(t, 1H), 7.06(s,1H), 6.78 (bm,1H), 6.16(q, 1H),4.95(s, 2H), 3.73(m, 4H), 3.59(m,2H), 2.62(m, 2H),2.51(m, 4H),1.87(d, 3H). 517[M + 1] I-391

(3-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone 0.098 4 as inExampleI-387 (300 MHz, CDCl3) δ 7.86(d, 1H), 7.37(m,4H),7.30(d, 2H), 7.15(t, 1H),7.02(s, 1H), 6.15(m, 1H), 4.91(s,2H), 4.45(m,1H), 3.41(m, 2H),2.70(m, 4H), 1.84(d, 3H), 1.70–2.0(m, 10H) 541[M + 1]I-392

3-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide 0.072 4 as inExampleI-387 (300 MHz, CDCl3) δ 8.60 (bm, 1H), 7.89(s,1H),7.65(d, 1H), 7.45(m, 3H),7.32(d, 2H), 7.15(t, 1H), 7.04(s,1H), 6.17(q,1H), 4.89(s, 2H),3.62(m, 2H), 2.78(m, 2H), 2.66(m,4H), 1.86(d, 3H),1.83(m, 2H),1.79(m, 4H). 513[M + 1] I-393

N-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzamide 0.079 4 as inExampleI-387 (300 MHz, CDCl3) δ 7.88(s, 1H), 7.81(s,1H),7.63(d, 1H), 7.48(m, 3H),7.32(d, 2H), 7.15(t, 1H), 7.06(s,1H), 6.69 (bm,1H), 6.16(q, 1H),4.94(s, 2H), 3.65(m, 4H), 3.50(m,2H), 2.62(m, 2H),2.52(m, 4H),2.09(s, 3H), 1.87(d, 3H). 556[M + 1] I-394

3-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide 0.061 4 as inExampleI-387 (300 MHz, CDCl3) δ 7.89(s, 1H), 7.73(s,1H),7.65(d, 1H), 7.50(d; 1H),7.43(t, 1H), 7.32(d, 2H), 7.16(t,1H), 7.04(s,1H), 6.15(m, 1H),6.05 (bd, 1H), 4.92(s, 2H), 4.03(m,1H), 2.94(m, 2H),2.38(s, 3H),2.26(m, 2H), 2.09(m, 2H), 1.86(d, 3H), 1.70(m, 2H). 499[M +1] I-395

(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone 0.058 4 as inExampleI-387 (300 MHz, CDCl3) δ 7.85(s, 1H), 7.40(m,4H),7.30(d, 2H), 7.16(t, 1H),7.02(s, 1H), 6.15(m, 1H), 4.93(s,2H), 3.82(m,2H), 3.45(m, 2H),2.52(m, 2H), 2.38(m, 2H), 2.33(s,3H), 1.86(d, 2H).487[M + 1] I-396

(3-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone 0.18 4 as inExampleI-387 (300 MHz, CDCl3) δ 7.86(d, 1H), 7.37(m,4H),7.30(d, 2H), 7.15(t, 1H),7.02(s, 1H), 6.15(m, 1H), 4.91(s,2H), 4.45(m,1H), 3.41(m, 2H),2.70(m, 4H), 1.84(d, 3H), 1.70–2.0(m, 10H) 541[M + 1]I-397

(3-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone 0.055 4 as inExampleI-387 (300 MHz, CD3OD) δ 7.74(s, 1H), 7.69–7.43(m,6H), 7.32(t, 1H), 7.22(s, 1H),6.42(m, 1H), 4.05–3.60(m, 4H),3.50(m, 1H),2.50(m, 1H), 2.18(m, 1H), 1.90(d, 3H). 471[M + 1] I-398

(3-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone 0.072 4 as inExampleI-387 (300 MHz, CD3OD) δ 7.74(s, 1H), 7.69–7.43(m,6H), 7.32(t, 1H), 7.22(s, 1H),6.42(m, 1H), 4.05–3.60(m, 4H),3.50(m, 1H),2.50(m, 1H), 2.18(m, 1H), 1.90(d, 3H). 471[M + 1] I-399

4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid3 as inExampleI-211 403[M + 1] I-400

4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide 0.059 4 (300 MHz, CDCl3) δ 7.89(s, 1H), 7.79(d, 2H), 7.43(d, 2H),7.32(d, 2H),7.15(t, 1H), 7.02(s, 1H), 6.87(bm, 1H), 6.15(q, 1H), 4.93(s,2H),3.58(m, 2H), 2.72(m, 2H), 2.58(m,4H), 1.87(d, 3H), 1.80(m, 4H).501[M + 1] I-401

4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide 0.073 4 as inExampleI-400 (300 MHz, CDCl3) δ 7.90(s, 1H), 7.79(d, 2H),7.44(d, 2H), 7.32(d, 2H),7.15(t, 1H), 7.03(s, 1H), 6.77(bm, 1H), 6.15(q,1H), 4.95(s, 2H),3.74(m, 4H), 3.57(m, 2H), 2.61(m,2H), 2.52(m, 4H),1.87(d, 3H). 515[M + 1] I-402

(4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone 0.068 4 as inExampleI-400 (300 MHz, CDCl3) δ 7.87(s, 1H),7.52(m, 2H),7.39(d, 2H), 7.31(d,2H), 7.15(t, 1H), 7.01(s, 1H),6.15(q, 1H), 4.91(s,2H), 4.45(m,1H), 3.41(m, 2H), 2.70(m, 4H),1.86(d, 3H), 1.70–2.0(m, 10H)539[M + 1] I-403

4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide 0.062 4 as inExampleI-400 (300 MHz, CDCl3) δ 7.89(s, 1H),7.76(d, 2H),7.42(d, 2H), 7.31(d,2H), 7.15(t, 1H), 7.02(s, 1H),6.15(q, 1H), 5.97 (bd,1H), 4.94(s, 2H), 4.03(m, 1H), 2.85(m,2H), 2.32(s, 3H),2.18(m, 2H),2.06(m, 2H), 1.86(d, 3H), 1.60(m, 2H). 501[M + 1] I-404

(4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone 0.052 4 as inExampleI-400 (300 MHz, CDCl3) δ 7.88(s, 1H),7.41(m, 4H),7.32(d, 2H), 7.15(t,1H), 7.02(s, 1H), 6.15(q, 1H),4.92(s, 2H), 4.62(m,1H), 3.66(m, 1H), 2.82(m, 2H), 2.68(m, 1H),2.40(m, 1H), 1.87(d,3H), 1.65(m, 1H), 1.15(d, 3H), 0.98(d, 3H). 499[M + 1] I-405

N-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzamide 0.062 4 as inExampleI-400 (300 MHz, CDCl3) δ 7.90(s, 1H),7.78(d, 2H),7.44(d, 2H), 7.32(d,2H), 7.15(t, 1H), 7.03(s, 1H),6.69 (bm, 1H), 6.15(q,1H), 4.96(s, 2H), 3.66(m, 2H), 3.61(m, 2H),3.50(m, 2H), 2.62(m,2H), 2.52(m,4H), 2.10(s, 3H), 1.87(d, 3H). 556[M + 1] I-406

4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide 0.061 4 as inExampleI-400 (300 MHz, CDCl3) δ 8.80 (bm, 1H),7.90(s, 1H),7.79(d, 2H), 7.40(d,2H), 7.31(d, 2H), 7.15(t, 1H),7.02(s, 1H), 6.15(q,1H), 4.91(s, 2H), 3.62(m, 2H), 2.78(m, 2H),2.66(m, 4H), 1.87(d,3H), 1.85(m, 4H), 1.25(m, 2H). 513[M + 1] I-407

(4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-aminopyrrolidin-1-yl)-methanone 0.05 4 as inExampleI-400 (300 MHz, CD3OD) δ 7.74–7.24(m, 9H),6.39(m,1H), 4.05–3.60(m, 4H),3.50(m, 1H), 2.50(m, 1H), 2.18(m,1H), 1.90(d, 3H).471[M + 1] I-408

(4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone 0.049 4 as inExampleI-400 (300 MHz, CD3OD) δ 7.74–7.24(m, 9H),6.39(m,1H), 4.05–3.60(m, 4H),3.50(m, 1H), 2.50(m, 1H), 2.18(m,1H), 1.90(d, 3H).471[M + 1] I-409

(4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone 0.081 4 as inExampleI-400 (300 MHz, CDCl3) δ 7.87(s, 1H), 7.52(m,2H),7.39(d, 2H), 7.31(d, 2H), 7.15(t, 1H), 7.01(s, 1H), 6.15(q, 1H),4.91(s,2H), 4.45(m, 1H), 3.41(m,2H), 2.70(m, 4H), 1.86(d, 3H),1.70–2.0(m, 10H)539[M + 1] I-410

(4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone 0.055 4 as inExampleI-400 (300 MHz, CDCl3) δ 7.87(s, 1H), 7.39(m,4H),7.32(d, 2H), 7.17(t, 1H), 7.01(s, 1H), 6.15(q, 1H), 4.91(s, 2H),4.60(m,1H), 3.76(m, 1H), 3.00(m,2H), 2.60(m, 4H), 2.28(m, 1H),1.95(m, 2H),1.86(d, 3H), 1.81(m,4H), 1.56(m, 2H). 541[M + 1] I-411

(4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone 0.053 4 as inExampleI-400 (300 MHz, CDCl3) δ 7.87(s, 1H), 7.40(m,4H),7.31(d, 2H), 7.15(t, 1H), 7.01(s, 1H), 6.15(q, 1H), 4.92(s, 2H),3.78(m,2H), 3.52(m, 2H), 2.41(m,4H), 2.34(s, 3H), 1.86(d, 3H). 487[M + 1] I-412

(S)-2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylicacid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-amide 0.067 11 (300 MHz, CDCl3) δ 9.05(br, 1H), 7.70(s,1H), 7.05(t, 1H),6.70(s, 1H), 6.02(q, 1H), 5.01(s, 2H), 4.15(dd, 2H),3.75(m, 2H), 3.25(m,1H), 2.75(m,3H), 2.45(m, 3H), 2.05(m, 1H),1.78(d, 3H), 1.65(br, 7H).534[M + 1] I-413

4-Methyl-piperazine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-amide 0.056 11 (300 MHz, CDCl3) δ 7.75(s, 1H), 7.30(m,2H), 7.05(t, 1H),6.75(s, 1H),6.02(q, 1H), 5.01(s, 2H), 4.20(d,2H), 3.45(m, 4H), 2.45(m,4H),2.25(s, 3H), 1.81(d, 3H). 480[M + 1] I-414

4-Pyrrolidin-1-yl-piperidine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-amide 0.058 11 (300 MHz, CDCl3) δ 7.75(s, 1H), 7.30(m,2H), 7.10(t, 1H),6.70(s, 1H),6.02(q, 1H), 5.01(s, 2H), 4.20(d,2H), 3.89(d, 1H) 2.89(t,2H),2.55(s, 4H), 2.21(m, 2H), 1.90(d, 2H),1.81 (d, 3H), 1.45(m, 2H),1.25(m, 2H). 534[M + 1] I-415

(3R,5S)-3,5-Dimethyl-piperazine-1-carboxylicacid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-amide 0.063 11 (300 MHz, CDCl3) δ 7.75(s, 1H), 7.30(m,2H), 7.05(t, 1H),6.75(s, 1H),6.02(q, 1H), 5.01(s, 2H), 4.78(s,1H), 4.20(d, 2H), 3.85(d,1H),2.85(m, 4H), 2.45(t, 1H), 1.89(s, 3H),1.01(d, 6H). 494[M + 1] I-416

1-(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-3-(1-methyl-piperidin-4-yl)-urea 0.051 11 (300 MHz, CDCl3) δ 7.75(s, 1H), 7.30(m,2H), 7.05(t, 1H),6.70(s, 1H),6.00(q, 1H), 5.25(m, 1H), 5.05(s,2H), 4.80(d, 1H), 4.15(d,2H),2.75(d, 2H), 2.20(s, 3H), 2.10(t, 2H),1.95(d, 2H), 1.75 (d, 3H),1.45(d, 2H). 494[M + 1] I-417

1-(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-3-(3-pyrrolidin-1-yl-propyl)-urea 0.062 11 (300 MHz, CDCl3) δ 7.70(s, 1H), 7.30(m,2H), 7.05(t, 1H),6.70(s, 1H),6.00(q, 1H), 5.30(m, 1H), 5.01(s,2H), 4.15(d, 2H), 3.25(m,2H),2.50(m, 6H), 1.80(d, 3H), 1.82(m, 4H),1.60(m, 2H). 508[M + 1] I-418

1-(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea 0.052 11 (300 MHz, CDCl3) δ 7.70(s, 1H), 7.30(m,2H), 7.05(t, 1H),6.70(s, 1H),6.00(q, 1H), 5.45(s, 1H), 5.15(s,2H), 4.15(d, 2H), 3.25(m,2H),2.60(t, 2H), 2.50(m, 4H), 1.80(d, 3H),1.70(s, 4H). 496[M + 1] I-419

1-(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-3-(2-morpholin-4-yl-ethyl-urea 0.055 11 (300 MHz, CDCl3) δ 7.73(s, 1H), 7.28(m,2H), 7.05(t, 1H),6.70(s, 1H),6.00(q, 1H), 5.25(s, 1H), 5.15(s,2H), 4.15(d, 2H), 3.65(m,4H),3.25(m, 2H), 2.45(m, 6H), 1.80(d, 3H). 510[M + 1] I-420

1-(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-3-(3-morpholin-4-yl-propyl)-urea 0.064 11 (300 MHz, CDCl3) δ 7.70(s, 1H), 7.30(m,2H), 7.05(t, 1H),6.70(s, 1H),6.00(q, 1H), 5.10(s, 2H), 4.15(d,2H), 3.70(m, 6H), 3.20(s,2H),2.50(m, 4H), 1.80(d, 3H), 1.65(m, 2H). 524[M + 1] I-421

(R)-2-Pyrrolidin-1-ylmethyl-pyrrolidin3-1-carboxylicacid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl-amide0.071 11 (300 MHz, CDCl3) δ 9.05(br, 1H),7.70(s, 1H), 7.05(t, 1H),6.70(s, 1H),6.02(q, 1H), 5.01(s, 2H), 4.15(dd, 2H),3.75(m, 2H), 3.25(m,1H), 2.75(m, 3H),2.45(m, 3H), 2.05(m, 1H), 1.78(d, 3H),1.65(br, 7H).534[M + 1] I-422

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-dimethylamino-prop-1-ynyl)-pyridin-2-ylamine 0.071 11 382[M + 1] I-423

(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-area 0.062 11 397[M + 1] I-424

N-(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-2-piperidin-1--yl-acetamide 0.016 12 (300 MHz, CDCl3) δ 7.74(s, 1H),7.45 (bm, 1H), 7.31(dd, 1H),7.07(t, 1H),6.73(s, 1H), 6.00(q, 1H), 4.99(s, 2H),4.26(d, 2H), 2.98(s,2H), 2.46(m, 4H),1.81(d, 3H), 1.59(m, 4H), 1.45(m, 2H). 579[M + 1] I-425

N-(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-2-morpholin-4-yl-acetamide 0.027 12 (300 MHz, CDCl3) δ 7.74(s, 1H),7.45 (bm, 1H), 7.31(m, 2H),7.08(t, 1H),6.71(s, 1H), 6.00(q, 1H), 5.02(s, 2H),4.27(d, 2H), 3.73(m,4H), 3.05(s, 2H),2.54(m, 4H), 1.81(d, 3H). 481[M + 1] I-426

N-(3-{8-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-2-pyrrolidin-1-yl-acetamide<0.0091 12 (300 MHz, CDCl3) δ 7.74(s, 1H),7.37 (bm, 1H), 7.31(dd, 1H),7.08(t, 1H),6.72(s, 1H), 6.00(q, 1H), 5.01(s, 2H),4.27(d, 2H), 3.18(s,2H), 2.63(m, 4H),2.01(m, 2H), 1.81(d, 3H), 1.80(m, 2H). 465[M + 1] I-427

N-(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-2-((R)-3-hydroxy-pyrrolidin-1-yl)-acetamide 0.011 12 (300 MHz, CDCl3) δ 7.71(s, 1H),7.45 (bm, 1H), 7.31(dd, 1H),7.07(t, 1H),6.72(s, 1H), 5.99(q, 1H), 5.06(s, 2H),4.42(m, 1H), 4.25(m,2H), 3.21(s, 2H),3.00(m, 1H), 2.80(m, 1H), 2.71(m, 1H),2.45(m, 1H),2.22(m, 1H), 1.79(d, 3H),1.78 (m, 2H). 481[M + 1] I-428

N-(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-2-(4-hydroxy-piperidin-1-yl)-acetamide 0.012 12 (300 MHz, CDCl3) δ 7.73(d, 1H),7.38 (bm, 1H), 7.31(dd, 1H),7.08(dd, 1H),6.72(d, 1H), 6.00(q, 1H), 5.03(s, 2H), ,4.26(d, 2H),3.74(m, 1H), 3.02(s, 2H),2.78(m, 2H), 2.32(m, 2H), 1.92(m, 4H),1.80(d,3H). 495[M + 1] I-429

N-(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-2-dimethylamino-acetamide 0.022 12 (300 MHz, CDCl3) δ 7.73(d, 1H),7.38 (bm, 1H), 7.31(dd, 1H),7.08(dd, 1H),6.72(d, 1H), 6.00(q, 1H), 4.99(s, 2H),4.26(d, 2H), 2.98(s,2H), 2.31(s, 6H),1.80(d, 3H). 439[M + 1] I-430

N-(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-prop-2-ynyl)-2-diethylamino-acetamide 0.013 12 (300 MHz, CDCl3) δ 7.73(d, 1H),7.59 (bm, 1H), 7.30(dd, 1H),7.07(dd, 1H),6.72(d, 1H), 6.00(q, 1H), 4.98(s, 2H),4.25(d, 2H), 3.05(s,2H), 2.57(dd, 4H),1.80(d, 3H), 1.03(t, 6H). 467[M + 1] I-431

2-(4-Acetyl-piperazin-1-yl)-N-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]pyridin-3-yl}-prop-2-ynyl)-acetamide 0.027 12 (300 MHz, CDCl3) δ 7.73(d, 1H),7.31(dd, 1H), 7.25 (bm, 1H),7.08(dd, 1H),6.71(d, 1H), 6.00(q, 1H), 5.04(s, 2H), , 4.27(d, 2H),3.66(m, 2H), 3.52(m, 2H),3.08(s, 2H), 2.78(m, 2H), 2.32(m,2H), 2.53(m,4H), 2.10(s, 3H), 1.81(d, 3H). 522[M + 1] I-432

4-Methyl-piperazine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-amideKi 0.61 13 as inExampleI-412 (300 MHz, CDCl3) δ 7.73(d, 1H), 7.30(dd,1H), 7.07(t, 1H), 6.78(d, 1H),6.01(q, 1H), 5.01(s, 2H), 4.64(s,1H),3.38(m, 4H), 2.42(m, 4H), 2.31(s, 3H),1.79(d, 3H), 1.70(s, 6H).508[M + 1] I-433

(3R,5S)-3,5-Dimethyl-piperazine-1-carboxylicacid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-amideKi 1.5 11 (300 MHz, CDCl3) δ 7.74(s, 1H), 7.30(dd, 1H), 7.07(t, 1H),6.79(s, 1H),6.01(q, 1H), 4.93(s, 2H), 4.59(s, 1H),3.75(m, 2H), 2.82(m,2H), 2.35(m, 2H),1.80(d, 3H), 1.71(s, 6H), 1.09(d, 6H). 522[M + 1] I-434

(R)-2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylicacid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-amideKi 1.22 11 (300 MHz, CDCl3) δ 8.44(bs, 1H), 7.72(d, 1H), 7.30(dd, 1H),7.07(t, 1H),6.79(s, 1H), 6.01(q, 1H), 4.87(s, 2H),3.75(m, 1H), 3.25(m,1H), 2.68(m, 2H),2.56(m, 2H), 2.40(m, 1H), 2.05(m, 1H),1.82–1.68 (m,17H), 1.56(m, 1H). 562[M + 1] I-435

(S)-2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylicacid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-amideKi 1.58 11 (300 MHz, CDCl3) δ 8.44(bs, 1H), 7.72(s, 1H), 7.30(dd, 1H),7.07(t, 1H),6.79(s, 1H), 6.01(q, 1H), 4.87(s, 2H),3.75(m, 1H), 3.25(m,1H), 2.68(m, 2H),2.56(m, 2H), 2.40(m, 1H), 2.05(m, 1H),1.82–1.68 (m,17H), 1.56(m, 1H). 562[M + 1] I-436

1-(3-{6-Amino-5-[1-(2,6-dicloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-3-(2-morpholin-4-yl-ethyl)-ureaKi 1.11 11 (300 MHz, CDCl3) δ 7.72(s, 1H), 7.31(dd, 1H), 7.08(t, 1H),6.75(s, 1H),6.01(q, 1H), 5.53 (bm, 1H), 5.00(s, 2H),4.66(bs, 1H),3.56(m, 4H), 3.32(m, 2H),2.45(m, 2H), 2.35(m, 4H), 1.81(d,3H), 1.64(s,6H). 538[M + 1] I-437

1-(3-{6-Amino-5-[1-(2,6-dicloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-3-(2-pyrrolidin-1-yl-ethyl)-ureaKi 0.61 11 (300 MHz, CDCl3) δ 7.72(s, 1H), 7.31(dd, 1H), 7.08(t, 1H),6.77(s, 1H),6.01(q, 1H), 5.68 (bm, 1H), 5.14(bs, 1H),5.01(s, 2H),3.30(m, 2H), 2.65(m, 2H),2.50(m, 4H), 1.81(d, 3H), 1.68(m,4H), 1.63(s,6H). 522[M + 1] I-438

4-Pyrrolidin-1-yl-piperidine-1-carboxylic acid(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1,1-dimethyl-prop-2-ynyl)-amideKi 0.72 11 (300 MHz, CDCl3) δ 7.73(s, 1H), 7.31(dd, 1H), 7.07(t, 1H),6.79(s, 1H),6.01(q, 1H), 5.68 (bm, 1H), 4.95(s, 2H),4.68(bs, 1H),3.88(m, 2H), 2.82(m, 2H),2.58(m, 4H), 2.28(m, 1H), 1.92 (m,2H), 1.81(d,3H), 1.80(m, 4H), 1.70(s,6H), 1.50(m, 2H). 562[M + 1] I-439

3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-propynoicacidcyclohexylamide Ki 0.46 11 (300 MHz, CDCl3) δ 7.85(d, 1H), 7.31(dd,1H), 7.09(t, 1H), 6.78(d, 1H),6.00(q, 1H), 5.69 (bd, 1H), 5.14(s,2H),4.12 (m, 1H), 1.81(d, 3H), 1.20(d, 6H). 410[M + 1] I-440

3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-propynoicacidisopropylamide Ki 0.43 11 (300 MHz, CDCl3) δ 7.86(s, 1H), 7.31(dd,1H), 7.09(t, 1H), 6.79(s, 1H),6.00(q, 1H), 5.72 (bd, 1H), 5.14(s,2H),3.82(m, 1H), 1.95(m, 2H), 1.80(d, 3H),1.72(m, 2H), 1.65(m, 2H),1.38(m,2H), 1.20(m, 2H). 450[M + 1] I-441

4-(3-Amino-3-methyl-but-1-ynyl)-2-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-phenylamineKi 1.06 11 (300 MHz, CD3OD) δ 7.60(d, 1H), 7.45(dd, 1H), 7.25(t, 1H),6.66(d, 1H),6.06(q, 1H), 1.84(d, 3H), 1.66(s, 6H). 382[M + 1] I-442

(4-{6-Amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone16% at1 uM 13 (300 MHz, CDCl3) δ 7.90(s, 1H), 7.51(m, 1H), 7.40(m, 5H),7.10(m, 1H),6.90(s, 1H), 5.80(q, 1H), 4.94(s, 2H),3.58(m, 4H), 2.53(m,4H), 2.32(s, 3H),1.84(d, 3H). 503[M + 1] I-443

(4-{6-Amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1yl)-methanone13% at1 um 13 (300 MHz, CDCl3) δ 7.89(s, 1H), 7.54(m, 1H), 7.32(d, 5H),7.17(m, 1H),6.90(d, 1H), 5.79(q, 1H), 4.93(s, 2H),4.60(m, 1H), 3.80(m,1H), 2.95(m, 2H),2.64(m, 4H), 2.34(m, 1H), 1.95(m, 2H), 1.81(m,4H), 1.73(d,3H), 1.56(m, 2H). 557[M + 1] I-444

(4-{6-Amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone10% at1 uM 13 (300 MHZ, CDCl3) δ 7.9(d, 1H), 7.50(m, 1H), 7.36(m, 5H),7.11(m, 1H),6.90(s, 1H), 5.81(q, 1H), 4.93(s, 2H),4.62(m, 1H), 3.66(m,1H), 2.85(m, 2H),2.65(m, 1H), 2.40(m, 1H), 1.73(d, 3H), 1.10(m, 7H).517[M + 1] I-445

(4-{6-Amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone15% at1 uM 13 (300 MHz, CDCl3) δ 7.90(s, 1H), 7.73(m, 1H), 7.53(m, 3H),7.34(d, 2H),7.13(m, 1H), 6.90(s, 1H), 5.80(q, 1H),4.93(s, 2H), 4.45(m,1H), 3.50(m, 2H),2.70(m, 4H), 1.73(d, 3H), 1.20–2.0(m, 10H). 557[M + 1]I-446

(4-{6Amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone12% at1 uM 13 (300 MHz, CDCl3) δ 7.90(s, 1H), 7.73(m, 1H), 7.53(m, 3H),7.34(d, 2H),7.13(m, 1H), 6.90(s, 1H), 5.80(q, 1H),4.93(s, 2H), 4.45(m,1H), 3.50(m, 2H),2.70(m, 4H), 1.73(d, 3H), 1.20–2.0(m, 10H). 557[M + 1]I-449

4-[6-Amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide12% at1 uM 13 (300 MHz, CDCl3) δ 7.90(d, 1H), 7.75(d, 2H), 7.72(m, 1H),7.52(m, 1H),7.48(d, 2H), 7.10(m, 1H), 6.89(d, 1H),6.00 (bd, 1H), 5.80(q,1H), 4.93(s, 2H), 4.02(m, 1H), 2.85(m, 2H), 2.31(s, 3H), 2.16(m, 2H),2.05 (m,2H), 1.73(d, 3H), 1.62(m, 2H). 517[M + 1] I-450

4-{6-Amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide7% at1 uM 13 (300 MHz, CDCl3) δ 7.90(d, 1H), 7.79(d, 2H), 7.55(m, 2H),7.48(d, 2H),7.13(m, 1H), 7.08(bs, 1H), 6.90(s, 1H),5.80(q, 1H), 4.94(s,2H), 3.58(m, 2H),2.78(m, 2H), 2.62(m, 4H), 1.81(m, 4H),1.72(d, 3H).517[M + 1] I-451

4-{6-Amino-5-[1-(3-fluoro-3-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide12% at1 uM 13 (300 MHz, CDCl3) δ 7.91(d, 1H), 7.78(d, 2H), 7.51(m, 2H),7.39(d, 2H),7.10(m, 1H), 6.91(d, 1H), 6.78(bs, 1H),5.82(q, 1H), 4.97(s,2H), 3.72(m, 4H),3.57(m, 2H), 2.62(m, 2H), 2.52(m, 4H),1.73(d, 3H).533[M + 1] I-452

4-{6-Amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide3% at1 uM 13 (300 MHz, CDCl3) δ 8.81(s, 1H), 7.92(s, 1H), 7.78(d, 2H),7.53(m, 1H),7.48(d, 2H), 7.13(m, 1H), 6.90(s, 1H),5.80(q, 1H), 4.90(s,2H), 3.60(m, 2H),2.78(m, 2H), 2.66(m, 4H), 1.85(m, 6H),1.73(d, 3H).531[M + 1] I-453

4-{6-Amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-morpholin-4-yl-propyl)-benzamide10% at1 uM 13 (300 MHz, CDCl3) δ 7.93(s, 1H), 7.80(d, 2H), 7.53(m, 3H),7.38(d, 2H),7.10(m, 1H), 6.91(d, 1H), 5.82(q, 1H),4.95(s, 2H), 3.70(m,4H), 3.57(m, 2H),2.54(m, 6H), 1.81(m, 2H), 1.73(d, 3H). 547[M + 1] I-454

6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-nicotinonitrile 7%at1 uM ExampleI-454 (400 MHz, DMSO-d6) δ 7.93(s, 1H), 7.56(m, 1H),7.46(t, 1H), 6.88(br, 2H),6.76(s, 1H), 6.02(q, 1H), 1.77(d, 3H). 325[M −1] I-455

6-Amino-5-[1-(2,6-dichloro-3-cyano-phenyl)-ethoxy]-nicotinonitrile 6%at1 uM ExampleI-455 (400 MHz, DMSO-d6) δ 8.00(s, 1H), 7.81(d, 1H),7.07(t, 2H), 5.78(d, 1H),1.74(d, 3H). 332[M − 1] I-456

5-Aminomethyl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine0% at1 uM ExampleI-456 (400 MHz, DMSO-d6) δ 7.53(m, 1H), 7.43(m, 2H),6.76(s, 1H), 5.98(q, 1H),5.47(br, 2H), 1.74(d, 3H) 331[M + 1] I-457

(R)-2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylicacid{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylmethyl}-amide1% at1 uM ExampleI-457 (400 MHz, DMSO-d6) δ 9.58(s, 1H), 7.93(s, 1H),7.55(m, 1H), 7.40(s, 1H),6.59(dd, 1H), 6.80(d, 1H), 6.06(t, 1H),4.19(dd,1H), 4.10(dd, 1H), 3.94(dd,1H), 3.85(dd, 1H), 3.21(m, 2H),3.15(m, 2H),3.01(m, 2H), 1.98(m, 2H),1.90(m, 2H), 1.84(m, 2H), 1.78(d,3H), 1.72(br,1H). 511[M + 1] I-458

N-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylmethyl}-methanesulfonamide0% at1 uM as inExampleI-13 (400 MHz, DMSO-d6) δ7.51(m, 1H), 7.43(t, 2H),7.28(m, 1H), 6.70(s, 1H), 5.96(q,1H), 5.68(s, 2H), 3.84(d, 2H), 2.68(s,3H),1.76(d, 3H) 409[M + 1] I-459

N-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylmethyl}-acetamide2% at1 uM as inExampleI-14 (400 MHz, CDCl3): d 7.49(s, 1H), 7.29(m, 1H),7.06(t, 1H), 6.71(s, 1H),6.03(q, 1H), 5.49(bs, 1H), 4.82(bs,2H),4.29(dd, 1H), 4.12 (dd, 1H),1.96(s, 3H), 1.83(d, J 8.0 Hz, 3H). 372[M +1] I-460

N-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-ylmethyl}-4-methyl-benzenesulfonamide9% at1 uM as inExampleI-13 (400 MHz, CDCl3): d 7.69(d, 2H), 7.29(m, 4H),7.06(t, 1H), 6.69(s, 1H),5.98(q, 1H), 4.84(bs, 2H), 4.51(m,1H), 3.86(dt,2H), 2.43(s, 3H),1.83(d, J 8.0 Hz, 3H). 485[M + 1] I-461

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-vinyl-pyridin-2-ylamine Ki0.68 3 (400 MHz, CDCl3): d 7.56(s, 1H), 7.29(m, 1H), 7.05(t, 1H),6.91(s, 1H),6.19(dd, 1H), 6.07(q, 1H), 5.40(d,J 16 Hz, 1H), 5.02(d, J 12Hz, 1H),4.85(bs, 2H), 1.85(d, J 8.0 Hz, 3H). 327[M + 1] I-462

(S)-1-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-ethane-1,2-diol2% at1 uM ExampleI-462 (400 MHz, CDCl3): d 7.55(s, 1H), 7.29(m, 1H),7.05(t, 1H), 6.82(s, 1H),6.05(q, 1H), 4.82(bs, 2H), 4.63(m,1H), 3.54(m,4H), 1.83(d,J 8.0 Hz, 3H). 362[M + 1] I-463

(R)-1-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-ethane-1,2-diol2% at1 uM as inExampleI-462 (400 MHz, CDCl3): d 7.55(s, 1H), 7.29(m,1H), 7.05(t, 1H), 6.82(s, 1H),6.05(q, 1H), 4.82(bs, 2H), 4.63(m,1H),3.54(m, 4H), 1.83(d,J 8.0 Hz, 3H). 362[M + 1] I-464

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-pyrazol-4-yl)-pyridin-2-ylamineKi 0.10 3 (400 MHz, CDCl3): d 7.65(s, 2H), 7.52(s, 1H), 7.37(m, 1H),7.13(m, 1H),7.04(s, 1H), 6.17(q, J 8.0 Hz, 1H),1.93(d, J 8.0 Hz, 3H)367[M + 1] I-465

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamineKi 0.34 14 (400 MHz, CDCl3): d 7.71(s, 1H), 7.55(s, 2H), 7.37(m, 1H),7.06(m, 1H),6.87(s, 1H), 6.09(m, 1H), 4.26(t, J 8.0 Hz,2H), 2.96(t, J8.0 Hz, 2H),2.55(m, 4H), 1.87(d, J 8.0 Hz,3H), 1.26(m, 4H) 465[M + 1]I-466

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(2-diisopropylamino-ethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamine Ki 0.47 14 (400 MHz, CDCl3): d 7.76(s, 1H), 7.54(s, 1H), 7.46(s,1H), 7.28(m, 1H),7.04(m, 1H), 6.86(m, 1H), 6.08(m, 1H),4.05(t, J 8.0 Hz,2H), 2.83(t, 2H),1.86(d, J 4.0 Hz, 3H), 0.96(d, J 8.0 Hz,12H). 495[M +1] I-467

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamineKi 0.083 14 (400 MHz, CDCl3): d 7.72(s, 1H), 7.60(s, 1H), 7.50(s, 1H),7.38(m, 1H),7.13(m, 1H), 7.05(s, 1H), 6.19(m, 1H),4.61(m, 2H), 3.89(m,4H), 3.53(m, 2H),3.02(m, 4H), 1.93(d, J 8.0 Hz, 3H). 481[M + 1] I-468

5-Bromo-3-(3-fluoro-2-methoxy-benzyloxy)-pyridin-2-ylamine 8% at1 uM 15(400 MHz, DMSO-d6) δ 7.67(s, 1H), 7.43(d, 1H), 7.40(d, 1H), 7.33(t, 1H),7.20(m,1H), 6.00(s, 2H), 5.19(s, 2H),3.96(s, 3H) 328[M + 1] I-469

5-Bromo-3-[1-(3-fluoro-2-methoxy-phenyl)-ethoxy]-pyridin-2-ylamine 7%at1 uM 15 (400 MHz, DMSO-d6) δ 7.51(s, 1H), 7.25(d, 1H), 7.18(m, 1H),7.09(m, 1H), 6.94(s,1H), 6.02(s, 2H), 5.72(q, 1H),3.93(s, 3H), 1.57(d,3H) 342[M + 1] I-470

{4-[6-Amino-5-(3-fluoro-2-methoxy-benzyloxy)-pyridin-3-yl]-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone3% at1 uM 3 (400 MHz, DMSO-d6) δ 9.24(s, 1H), 8.61(d, 1H), 7.96(d, 1H),7.81(d, 2H), 7.57(d,1H), 7.43(d, 2H), 7.32(t, 1H),7.18(m, 1H), 5.34(s,2H), 3.91(s,3H), 3.39(m, 2H), 2.49(m, 4H),1.21(m, 6H). 465[M + 1] I-471

(4-{6-Amino-5-[1-(3-fluoro-2-methoxy-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone1% at1 μM 3 (400 MHz, DMSO-d6) δ 9.25(d, 1H), 8.64(d, 1H), 7.88(s, 1H),7.61(d, 2H), 7.53(d,2H), 7.46(s, 1H), 7.35(d, 1H),7.21(s, 1H), 7.13(m,1H), 6.03(m,1H), 3.93(s, 3H), 3.38(m, 2H),2.49(m, 4H), 1.67(d, 3H),1.20(m, 6H) 479[M + 1] I-472

5-Bromo-3-(3-fluoro-2-isopropoxy-benzyloxy)-pyridin-2-ylamine Ki 12.1 15(400 MHz, DMSO-d6) δ 7.59(s, 1H), 7.36(d, 1H), 7.31(d, 1H), 7.25(t, 1H),7.12(m, 1H), 5.90(s, 2H), 5.10(s, 2H),4.43(m, 1H), 1.26(d, 6H) 356 I-473

{4-[6-Amino-5-(3-fluoro-2-isopropoxy-benzyloxy)-pyridin-3-yl]-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanoneKi 12.7 3 (400 MHz, DMSO-d6) δ 9.45(d, 1H), 8.79(q, 1H), 7.99(s, 1H),7.88(s, 1H), 7.80(d, 2H), 7.58(d, 2H), 7.41(d, 1H),7.32(t, 1H), 7.17(m,1H), 5.37(s,2H), 4.45(m, 1H), 3.40(m, 2H),2.49(m, 4H), 1.28(d, 8H),1.20(m, 6H) 493 I-474

5-(4-Amino-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine3 (400 MHz, DMSO-d6) δ 7.66(d, 1H), 7.55(q, 1H), 7.43(t, 1H), 7.02(d,2H), 6.81(s, 1H), 6.56(d, 2H), 6.08(q, 1H),5.60(s, 2H), 5.08(s, 2H),1.78(d,3H) 393 I-475

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-aceticacidmethyl ester Ki 0.20 as inExampleI-55 (400 MHz, CDCl3): d 7.82(s,1H), 7.30(m, 3H), 7.06(m, 1H), 6.95(m, 3H), 6.12(q, 1H), 4.80(m, 2H),4.66(s, 2H),3.82(s, 3H), 1.86(d, J 8.0 Hz, 3H). 467 I-476

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-aceticacid Ki 0.20 as inExampleI-55 (400 MHz, CDCl3): d 7.70(s, 1H), 7.50(m,2H), 7.45(m, 2H), 7.20(m, 2H), 6.85(m, 2H), 6.05(q, 1H), 5.72(s,2H),4.49(s, 2H), 3.82(s, 3H), 1.75(d, J 8.0 Hz, 3H). 453 I-477

2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-1-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-ethanoneKi 0.027 4 (400 MHz, CDCl3): d 7.48(s, 1H), 7.35(m, 1H), 7.20(m, 2H),7.12 (m, 2H), 7.01(m, 2H), 6.20(q, 1H), 4.73(m, 3H),4.10(m, 1H), 3.36(m,1H), 3.13(m, 2H), 2.84(m, 1H), 1.94(d, J 8.0 Hz,3H), 1.34(m, 6H). 548I-478

2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-1-((R)-3-hydroxy-pyrrolidin-1-yl)-ethanoneKi 0.041 4 (400 MHz, CDCl3): d 7.48(s, 1H), 7.36(m, 1H), 7.21(d, 2H),7.19(m, 2H), 7.10(m, 2H), 7.01(m, 2H), 6.20(q, 1H),4.65(m, 2H), 4.55(m,1H), 3.69(m, 3H), 3.48(m, 1H), 2.10(m, 3H), 1.92(m, 5H). 521 I-479

4-[2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-acetyl]-piperazine-1-carboxylicacid tert-butyl ester Ki 0.16 4 (400 MHz, CDCl3): d 7.50(s, 1H), 7.36(m,1H), 7.22(d, 2H), 7.19(m, 2H), 7.15(m, 2H), 7.00(m, 2H), 6.20(q,1H),4.75(s, 2H), 3.57(m, 4H), 3.45(m, 4H), 1.93(d, J 8.0 Hz, 3H),1.47(s, 9H). 620 I-480

2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-1-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethanone4 (400 MHz, CDCl3): d 7.48(s, 1H), 7.36(m, 1H), 7.20(d, 2H), 7.15(m,2H), 7.00(d, 2H), 6.20(q, 1H), 4.68(s, 2H),4.46(m, 1H), 4.04(m, 1H),3.93(m, 1H), 3.60(m, 1H), 3.52(m, 1H),3.50(m, 1H), 3.12 (m, 1H), 3.09(m,1H),2.83(m, 1H), 1.93(d, J 8.0 Hz,3H), 2.16–1.66(m, 10H). 588 I-481

5-Bromo-3-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-pyridin-2-ylamine15 (400 MHz, DMSO-d6) δ 7.57(d, 1H), 7.16(m, 3H), 6.95(dt, 1H), 6.07(d,2H), 5.63(d,1H), 2.10(m, 2H), 2.16(m, 2H), 1.86(m, 1H), 1.77(m, 2H),1.34(m, 1H). 352 I-482

{4-[6-Amino-5-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-pyridin-3-yl]-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone3 493 I-483

3-(3-FIuoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-5-[4-(2-pyrralidin-1-yl-ethoxy)-phenyl]-pyridin-2-ylamine3 462 I-484

N-{4-[6-Amino-5-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide3 442 I-485

3-(3-Fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-5-(1H-pyrazol-4-yl)-pyridin-3-ylamine3 337[M − 1] I-486

5-Bromo-3-[1-(2-chloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine 0% at1uM 15 (400 MHz, CDCl3): d 7.68(s, 1H), 7.24(m,3H), 6.69(s, 1H), 5.64(q,1H),4.78(bs, 2H), 1.68(d, J 8.0 Hz, 3H). 347 I-487

3-[1-(2-Chloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-2-ylamineKi 3.30 3 (400 MHz, CDCl3): d 7.50(s, 1H), 7.30(m,2H), 7.20(m, 3H),7.00(s, 1H),6.95(m, 2H), 5.90(q, 1H), 4.36(m, 2H),3.85(m, 2H), 3.55(m,2H), 2.95(m, 2H),2.10(m, 4H), 1.82(d, J 8.0 Hz, 3H). 456 I-488

5′-Benzyloxy-[2,3′]bipyridinyl-6′-ylamine >20 16 (CDCl3) d 5.15(br s,2H), 5.19(s, 2H),7.17(m, 1H), 7.34–7.46(m, 5H), 7.64(d,J=8 Hz, 1H),7.70(td, J=7.8, 1.9 Hz, 1H),7.86(d, J=1.6 Hz, 1H), 8.22(d, J=2 Hz,1H),8.63(d, J=4 Hz, 1H). 278 I-489

5-Benzyloxy-[3,3′]bipyridinyl-6-ylamine >20 16 (CDCl3) d 5.17(s, 2H),5.27(br s, 2H),7.19(d, J=2 Hz, 1H), 7.33(dd, J=7.8,4.6 Hz, 1H),7.35–7.44(m, 5H, 7.70(dt,J=2, 8 Hz, 1H), 7.85(d, J=2 Hz, 1H), 8.56(dd,J=1.6, 4.8 Hz, 1H), 8.71(d, J=2Hz, 1H). 278 I-490

3-Benzyloxy-5-pyrimidin-5-yl-pyridin-2-ylamine >20 16 (CDCl3) d 5.22(s,2H), 6.15(brs, 2H),7.21(s, 1H), 7.43(m, 5H), 7.77(s, 1H),8.81(s, 2H),9.20(s, 1H). 279 I-491

5-Benzyloxy-[3,3′]bipyridinyl-6,6′-diamine >20 16 (CDCl3) d 4.40(br s,2H), 4.94(br s, 2H),5.13(s, 2H), 6.58(d, J=8.4 Hz, 1H),7.09(d, J=1.6 Hz,1H), 7.35–7.44(m,5H), 7.56(dd, J=2.4, 8.4 Hz, 1H), 7.77(d,J=1.6 Hz, 1H),8.13(d, J=2 Hz, 1H). 293 I-492

5′-(2-Chloro-benzyloxy)-[2,3′]bipyridinyl-6′-ylamine  8.24 16 (CDCl3) d5.33(s, 2H), 5.99(bs, 2H), 7.22–7.26(m, 1H), 7.29–7.37(m,2H),7.42–7.51(m, 2H), 7.63(d, 1H), 7.72(dt,1H), 7.99(d, 1H), 8.13(d,1H), 8.65(dd, 1H). 312 I-493

5-(2-Chloro-benzyloxy)-[3,3′[bipyridinyl-6-ylamine  4.6 16 312 I-494

3-(2-Chloro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine 19.3 16 313I-495

5-(2-Chloro-benzyloxy)-[3,3′]bipyridinyl-6,6′-diamine  4.31 16 317 I-496

5′-(4-Chloro-benzyloxy)-[2,3′]bipyridinyl-6′-ylamine 14 16 (CDCl3) d5.18(s, 2H), 5.48(bs, 2H), 7.19–7.22(m, 1H), 7.38(s, 4H),7.63–7.65(m,1H), 7.73(dt, 1H), 7.89(d, 1H),8.17(d, 1H), 8.63(d, 1H). 312I-497

5-(4-Chloro-benzyloxy)-[3,3′]bipyridinyl-6-ylamine 14.1 16 312 I-498

3-(4-Chloro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine >20.0 16 313I-499

5-(4-Chloro-benzyloxy)-[3,3′]bipyridinyl-6,6′-diamine >20.0 16 317 I-500

5′-(2-Chloro-3,6-difluoro-benzyloxy)-[2,3′]bipyridinyl-6′-ylamine  1.816 (CDCl3) δ 5.39(s, 2H), 6.19(bs, 2H), 7.08(dt, 1H), 7.21-7.28(m, 2H),7.65(d, 1H),7.77(dt, 1H), 8.13(d, 1H), 8.67(dd, 1H) 348 I-501

5-(2-Chloro-3,6-difluoro-benzyloxy)-[3,3′]bipyridinyl-6-ylamine  0.28216 348 I-502

5-(2-Chloro-3,6-difluoro-benzyloxy)-[3,4′]bipyridinyl-6-ylamine  0.21116 348 I-503

3-(2-Chloro-3,6-dlfluoro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine 2.15 16 349 I-504

5-(2-Chloro-3,6-difluoro-benzyloxy)-[3,3′]bipyridinyl-6,6′-diamine 0.209 16 363 I-505

5′-(2,6-Dichloro-benzyloxy)-[2,3′]bipyridinyl-6′-ylamine  2.84 16(CDCl3) d 5.47(s, 2H), 5.76(bs, 2H), 7.21–7.25(m, 1H), 7.27–7.32(m,1H),7.37–7.41(m, 2H), 7.66(d, 1H), 7.75(dt,1H), 8.06(d, 1H), 8.17(d,1H), 8.66(dd, 1H). 346 I-506

5-(2,6-Dichloro-benzyloxy)-[3,3′]bipyridinyl-6-ylamine  2.71 16 346I-507

5-(2,6-Dichloro-benzyloxy)-[3,4′]bipyridinyl-6-ylamine  1.3 16 346 I-508

3-(2,6-Dichloro-benzyloxy)-pyrimidin-5-yl-pyridin-2-ylamine 10.3 16 347I-509

5-(2,6-Dichloro-benzyloxy)-[3,3′]bipyridinyl-6,6′-diamine  0.578 16 361I-510

5-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6,6′-diamine 0.0167 16 (CDCl3) d 1.87(d, J=6.6 Hz, 3H), 4.60(br s, 2H), 4.96(br s,2H), 6.11(q, J=6.6 Hz, 1H), 6.56(d, J=8.4 Hz, 1H), 6.91(s, 1H), 7.06(t,J=8.5 Hz, 1H), 7.31(dd,J=4.8, 8.7 Hz, 1H), 7.48(dd, J=1.8, 8.4 Hz,1H),7.75(s, 1H), 8.05(s, 1H). 393 I-511

{6′-Amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-4-yl}-(4-methyl-piperazin-1-yl)-methanone 0.0742 16 (CDCl3) d 1.87(d, J=6.6 Hz, 3H), 2.37(s, 3H), 2.39(br s, 2H),2.56(br s, 2H),3.43(br s, 2H), 3.86(br s, 2H), 5.13(br s, 2H), 6.21(q,J=6.7 Hz, 1H), 7.04(dd, J=8.1, 8.7 Hz, 1H), 7.10(dd, J=1.2,5.1 Hz, 1H),7.29(dd, J=5.1, 9.3 Hz,1H), 7.48(s, 1H), 7.57(d, J=1.5 Hz, 1H),8.24(d,J=1.8 Hz, 1H), 8.65(dd,J=0.6, 4.8 Hz, 1H). 504 I-512

{6′-Amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-6-yl}-(4-methyl-piperazin-1-yl)-methanone 0.0629 16 (CDCl3) d 1.87(d, J=6.6 Hz, 3H), 2.36(s, 3H), 2.46(m, 2H),2.58(m, 2H), 3.66(m, 2H), 3.89(m, 2H), 5.08(br s, 2H),6.17(q, J=6.6 Hz,1H), 7.05(dd, J=8.1, 8.8 Hz, 1H), 7.31(dd, J=5.0,8.9 Hz, 1H), 7.46(dd,J=0.8, 7.7 Hz, 1H),7.51(d, J=1.8 Hz, 1H), 7.55(dd, J=0.8,8.0 Hz, 1H),7.76(t, J=7.5 Hz, 1H),8.27(d, J=1.2 Hz, 1H). 504 I-513

{6′-Amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-5-yl}-(4-methyl-piperazin-1-yl)-methanone 0.034 16 (CDCl3) d 1.88(d, J=6.6 Hz, 3H), 2.38(s, 3H), 2.44(m, 2H),2.56(m, 2H), 3.52(m, 2H), 3.87(m, 2H), 5.05(br s, 2H),6.12 (q, J=6.7 Hz,1H), 6.97(d, J=1.8 Hz, 1H), 7.08(dd, J=8.1,8.7 Hz, 1H), 7.33(dd, J=5.0,8.9 Hz, 1H),7.72 (t, J=2.1 Hz, 1H), 7.86(d,J=2.1 Hz, 1H), 8.54(d, J=1.8Hz,1H), 8.65(d, J=2.4 Hz, 1H). 504 I-514

{6′-Amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-yl}-(4-methyl-piperazin-1-yl)-methanone 0.0213 16 (CDCl3) d 1.88(d, J=6.9 Hz, 3H), 2.39(s, 3H), 2.52(br s, 2H),2.61(br s, 2H),3.74(br s, 2H), 3.89(br s, 2H), 5.02(br s,2H), 6.12 (q,J=6.7 Hz, 1H), 6.97(d, J=1.2 Hz, 1H), 7.08(t, J=8.4 Hz, 1H), 7.33(dd,J=4.8, 8.7 Hz, 1H), 7.68(d, J=9 Hz, 1H), 7.76(dd, J=1.8, 8.4 Hz,1H),7.89(d, J=1.5 Hz, 1H), 8.59(d,J=1.5 Hz, 1H). 504 I-515

{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,4′]bipyridinyl-2′-yl}-(4-methyl-piperazin-1-yl)-methanone 0.0387 16 (CDCl3) d 1.88(d, J=6.9 Hz, 3H), 2.39(s, 3H), 2.51(m, 2H),2.61(m, 2H), 3.67(m, 2H), 3.90(m, 2H), 5.08(br s, 2H), 6.14(q, J=6.7 Hz,1H), 7.05(s, 1H), 7.06(dd,J=7.8, 9 Hz, 1H), 7.32(d, J=5.1 Hz,1H),7.34(dd, J=5.0, 7.7 Hz, 1H),7.66 (d, J=1.2 Hz, 1H), 8.00(d, J=1.8 Hz,1H), 8.53(d, J=5.1 Hz, 1H). 504 I-516

5-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6,6′-diamine 0.0393 16 (CDCl3) d 1.83(d, J=6.6 Hz, 3H), 4.55(br s, 2H), 4.87(br s,2H), 5.95(q, J=6.5 Hz, 1H), 6.55(d, S =8.4 Hz, 1H),6.93–7.12 (m, 3H),7.48(dd, J=1.8,8.4 Hz, 1H), 7.76(s, 1H), 8.09(s, 1H). 377 I-517

{6′-Amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-5-yl}-(4-methyl-piperazin-1-yl)-methanone 0.131 16 (CDCl3) d 1.84(d, J=6.6 Hz, 3H), 2.39(s, 3H), 2.53(br s, 4H),3.63(br s, 2H),3.82(br s, 2H), 5.09(br s, 2H), 6.06(q,J=6.5 Hz, 1H),6.93–7.10(m, 2H),7.60(d, J=7.8 Hz, 1H), 7.69(d,J=7.8 Hz, 1H), 7.76(dd,J=2.1, 8.4 Hz,1H), 8.28 (d, J=1.5 Hz, 1H),8.66(d, J=1.5 Hz, 1H). 488I-518

{6′-Amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-4-yl}-(4-methyl-piperazin-1-yl)-methanone 0.209 16 (CDCl3) d 1.84(d, J=6.6 Hz, 3H), 2.40(s, 3H), 2.45(br s, 2H),2.61(br s, 2H),3.48(br s, 2H), 3.89(br s, 2H), 5.13(br s,2H), 6.06(q,J=6.6 Hz, 1H), 6.93–7.10(m,2H), 7.12 (dd, J=1.2, 5.1 Hz, 1H),7.52(s,1H), 7.68(d, J=1.2 Hz, 1H), 8.24(d,J=1.8 Hz, 1H), 8.67(d, J=4.8Hz, 1H). 488 I-519

{6′-Amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-6-yl}-(4-methyl-piperazin-1-yl)-methanone 0.466 16 (CDCl3) d 1.84(d, J=6.6 Hz, 3H), 2.38(s, 3H), 2.49(m, 2H),2.60(m, 2H), 3.70(m, 2H), 3.91(m, 2H), 5.01(br s, 2H), 6.02(q, J=6.6 Hz,1H), 6.93–7.12 (m,2H), 7.49(dd, J=0.8, 7.7 Hz, 1H),7.58(dd, J=0.9, 8:1Hz, 1H), 7.62(d,J=1.8 Hz, 1H), 7.78(t,J=7.8 Hz, 1H), 8.29(d, J=1.8 Hz,1H). 488 I-520

{6′-Amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-5-yl}-(4-methyl-piperazin-1-yl)-methanone 0.134 16 (CDCl3) d 1.85(d, J=6.6 Hz, 3H), 2.44(s, 3H), 2.57(m, 4H),3.59(m, 2H), 3.91(m, 2H), 5.02(br s, 2H), 5.97(q, J=6.4 Hz,1H),6.96–7.14(m, 3H), 7.74(s, 1H), 7.87(br s, 1H), 8.57(br s, 1H), 8.71(brs, 1H). 488 I-521

{6′-Amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-yl}-(4-methyl-piperazin-1-yl)-methanone 0.0716 16 (CDCl3) d 1.86(d, J=6.6 Hz, 3H), 2.45(s, 3H), 2.62(br s, 2H),2.69(br s, 2H),3.82(br s, 2H), 3.95(br s, 2H), 4.97(br s,2H), 5.98(q,J=6.5 Hz, 1H), 6.96–7.14(m,3H), 7.71(d, J=8.1 Hz, 1H), 7.79(dd,J=2.3,8.3 Hz, 1H), 7.90(d, J=2.1 Hz,1H), 8.62(d, J=1.5 Hz, 1H). 488I-522

{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,4′]bipyridinyl-2′-yl}-(4-methyl-piperazin-1-yl)-methanone 0.0626 16 (CDCl3) d 1.86(d, J=6.6 Hz, 3H), 2.45(s, 3H), 2.62(br s, 2H),2.70(br s, 2H),3.77(br s, 2H), 3.96(br s, 2H), 5.03(br s,2H), 5.99(q,J=6.7 Hz, 1H), 6.96–7.14(m,2H), 7.16(d, J=1.8 Hz, 1H), 7.36(dd,J=2.0,5.3 Hz, 1H), 7.71(d, J=1.2 Hz,1H), 8.01(d, J=1.8 Hz, 1H),8.45(d,J=4.8 Hz, 1H). 488 I-523

5′-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-6′-ylamine 0.0677 16 (CDCl3) d 1.87(d, J=6.6 Hz, 3H), 5.20(br s, 2H), 6.23(q,J=6.7 Hz, 1H), 7.04(t, J=8.4 Hz, 1H), 7.15(dd, J=4.8,6.6 Hz, 1H),7.29(dd, J=5.1, 9.3 Hz, 1H),7.51(d, J=8.1 Hz, 1H), 7.59(d, J=1.2 Hz,1H), 7.67(td, J=7.8, 1.8 Hz,1H), 8.24(d, J=1.5 Hz, 1H),8.60(d, J=3.9 Hz,1H). 378 I-524

5′-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-6′-ylamine 0.612 16 (CDCl3) d 1.84(d, J=6.9 Hz, 3H), 5.14(br s, 2H), 6.08(q, J=6.5Hz, 1H), 6.93–7.10(m, 2H), 7.16(dd, J=5.1, 6.6 Hz,1H), 7.54(d, J=8.1 Hz,1H), 7.65–7.70(m, 2H), 8.24(s, 1H), 8.62(d, J=4.2 Hz, 1H) 362 I-525

5-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ylamine 0.0777 16 (CDCl3) d 1.87(d, J=6.6 Hz, 3H), 5.37(br s, 2H), 6.00(q.J=6.5 Hz, 1H), 6.97–7.15(m, 3H), 7.34(dd, J=4.7, 7.7 Hz,1H), 7.69(d,J=7.8 Hz, 1H), 7.82(s,1H), 8.56(d, J=3.9 Hz, 1H), 8.65(s, 1H). 362 I-526

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-pyrimidin-5-yl-pyridin-2-ylamine 0.552 16 (CDCl3) d 1.87(d, J=6.6 Hz, 3H), 5.16(br s, 2H), 5.98(q, J=6.5Hz, 1H), 6.96–7.14(m, 3H), 7.86(s, 1H), 8.77(s, 2H),9.14(s, 1H). 363I-527

{6′-Amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-5-yl}(4-methyl-piperazin-1-yl)-methanone 0.0385 16 (CDCl3) d 1.87(d, J=6.6 Hz, 3H), 2.38(s, 3H), 2.51(brs, 4H),3.62(br s, 2H), 3.81(br s, 2H), 5.13(br s, 2H), 6.21(q,J=6.7 Hz, 1H),7.04(t, J=8.4 Hz, 1H), 7.30(dd, J=4.8, 8.7 Hz, 1H), 7.75(dd,J=1.9, 8.2Hz, 1H),8.28(s, 1H), 8.64(s, 1H). 504 I-528

5-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-[3,4′]bipyridinyl-6-ylamine 0.0659 16 (CDCl3) d 1.84(d, J=6 Hz, 3H), 5.13(br s,2H), 5.97(q, J=6.5Hz, 1H), 6.95–7.10(m, 2H), 7.12 (d, J=1.6 Hz, 1H), 7.30(d,J=6 Hz, 2H),7.95(d, J=2 Hz, 1H),8.58(d, J=5.6 Hz, 2H). 362 I-529

5-Benzyloxy-3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-2-ylamine 2.58 17 (CDCl3) d 1.84(d, 3H), 4.88(s, 2H), 5.89(q,1H), 6.79(d, 1H),6. + 1(d, 1H), 7.01(dt, 1H), 7.11–7.17(m, 1H),7.28–7.40(m, 5H). 391I-530

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-(2-ethyl-butoxy)-pyridin-2-ylamine 4.08 17 385 I-531

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-(3-methyl-butoxy)-pyridin-2-ylamine 2.4 17 371 I-532

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-butoxy-pyridin-2-ylamine 1.94 17 357 I-533

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-propoxy-pyridin-2-ylamine 0.672 17 343 I-534

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-cyclohexylmethoxy-pyridin-2-ylamine 5.97 17 397 I-535

6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-ol  0.5417 301 I-536

3-[1-(2-Chloro-3,6-diftuoro-phenyl)-ethoxy]-5-(2-cyclohexyl-ethoxy)-pyridin-2-ylamine 7.5 17 411 I-537

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-isobutoxy-pyridin-2-ylamine 1.2 17 357 I-538

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-phenethyloxy-pyridin-2-ylamine 2.8 17 405 I-539

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-(pyridin-2-ylmethoxy)-pyridin-2-ylamine 3.2 17 392 I-540

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-(pyridin-4-ylmethoxy)-pyridin-2-ylamine 0.8 17 392 I-541

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone 0.079 4 as inExampleI-291 (300 MHz, CDCl3) δ 7.89(s, 1H), 7.40(m, 4H),7.35(dd, 1H), 7.08(t, 1H), 7.02(s,1H), 6.17(q, 1H), 4.98(s, 2H), 3.82(m,2H),3.62(m, 2H), 2.52(m, 4H), 1.88(d, 3H). 567

TABLE 3 Ki (μM) MS m/z No. Structure Name or I (%) ¹H-NMR (M + H)Procedure I-542

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone0.023 (400 MHz, DMSO-D6) d ppm 0.84(s, 3H) 0.93–1.10(m, 3H) 1.80(d,J=6.57 Hz, 3H) 2.30(s, 2H)2.55–2.74(m, 2H) 3.38–3.49(m, 1H) 4.32(s, 1H)5.96(s, 2H) 6.14(q, J=6.57 Hz, 1H)7.00(d, J=1.77 Hz, 1H) 7.36(m, 2H)7.45(m, 3H)7.56(dd, J=8.97, 4.93 Hz, 1H) 7.88(d,J=1.77 Hz, 1H) 51718/19/20/31 I-543

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone1.5 (400 MHz, DMSO-D6) d ppm 0.84(s, 3H) 0.93–1.10(m, 3H) 1.80(d, J=6.57Hz, 3H) 2.30(s,2H) 2.55–2.74(m, 2H) 3.38–3.49(m, 1H) 4.32(s, 1H) 5.96(s,2H) 6.14(q, J=6.57 Hz, 1H)7.00(d, J=1.77 Hz, 1H) 7.36(m, 2H) 7.45(m,3H)7.56(dd, J=8.97, 4.93 Hz, 1H) 7.88(d,J=1.77 Hz, 1H) 517 18/19/20/31I-544

5-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-fluoro-benzonitrile(400 MHz, DMSO-D6) d ppm 1.80(d, J=6.82 Hz,3H) 6.01(s, 2H) 6.17(q,J=6.57 Hz, 1H) 7.05(d, J=1.77 Hz, 1H) 7.44(t, J=8.72 Hz, 1H) 7.55(m, 2H)7.79(m, 1H) 7.89(d, J=1.77 Hz, 1H)7.97(dd, J=6.06, 2.27 Hz, 1H) 420 27I-545

4-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxyl]-pyridin-3-yl}-phenyl)-piperidin-4-ol(400 MHz, DMSO-D6) d ppm 1.49–1.65(m, 2H)1.75–1.86(m, 3H) 1.86–1.98(m,3H) 2.53 (s,1H) 2.88(s, 2H) 2.99(s, 2H) 5.84(s, 2H) 6.11(d, J=6.57 Hz,1H) 6.93(s, 1H) 7.28–7.38(m,J=8.08 Hz, 2H) 7.39–7.50(m, J=8.21, 8.21Hz,3H) 7.57(dd, J=8.72, 4.93 Hz, 1H) 7.81(s, 1H) 477 27 I-546

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-piperidin-1-yl-methanone0.057 (400 MHz, DMSO-D6) d ppm 1.43–1.56(m, 4H)1.61(d, J=3.79 Hz, 4H)1.81(d, J=6.57 Hz, 3H)3.51(s, 2H) 5.94(s, 2H) 6.15(d, J=6.82 Hz,1H)7.00(d, J=1.77 Hz, 1H) 7.28–7.41(m, 2H)7.40–7.50(m, 3H) 7.57(dd,J=9.09, 5.05 Hz,1H) 7.87(d, J=2.02 Hz, 1H) 488 20 I-547

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-pyrrolidin-1-yl-methanone0.067 (400 MHz, DMSO-D6) d ppm 1.73–1.93(m, 7H)3.39–3.52(m, 4H) 5.96(s,2H) 6.07–6.20(m,J=6.82 Hz, 1H) 6.99(d, J=1.77 Hz, 1H) 7.39–7.47(m, 3H)7.52(d, 2H) 7.56(dd, J=9.09. 5.05Hz, 1H) 7.82–7.92(m, J=1.77 Hz, 1H) 47420 I-548

4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-3-methyl-benzoicacid methylester 17% (400 MHz, CHLOROFORM-D) d ppm 1.77–1.88(m, 3H)2.11(s, 3H) 3.91(s, 3H) 4.90(s, 2H)6.02(d, J=6.82 Hz, 1H) 6.69(d, J=1.77Hz, 1H)7.00–7.09(m, 1H) 7.14(d, J=7.83 Hz, 1H) 7.26–7.31(m, 1H) 7.59(d,J=1.77 Hz, 1H) 7.83(dd,J=7.96, 1.39 Hz, 1H) 7.88(s, 1H) 450 19 I-549

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(dimethyl-piperazin-1-ylmethyl)-phenyl]-pyridin-2-ylamine0.095 (400 MHz, DMSO-D6) d ppm 0.84–0.96(m, 6H)1.44–1.61(m, 2H)1.72–1.83(m, 3H) 2.58–2.70(m, 2H) 2.71–2.84(m, 4H) 5.76–5.92 (m,2H)6.02–6.18(m, 1H) 6.88–7.01(m, 1H)7.25(d, 2H) 7.32(d, 2H) 7.38–7.49(m,1H)7.50–7.64(m, 2H) 7.76–7.88(m, 1H) 503 28 I-550

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-3,5-dimethoxy-phenyl)-(dimethyl-piperazin-1-yl)-methanone15% (400 MHz, DMSO-D6) d ppm 0.77–0.91(m, 3H)1.00(s, 3H) 1.75(d, J=6.82Hz, 3H) 2.16–2.30(m, J=12.63 Hz, 3H) 2.64–2.76(m, 3H) 3.54(s,6H)4.25–4.40(m, 1H) 5.69(s, 2H) 5.91(q,J=6.74 Hz, 1H) 6.54–6.67(m, 3H)7.37–7.43(m, 1H) 7.43–7.51(m, 1H) 7.51–7.60(m, 1H) 577 19/20 I-551

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-fluoro-phenyl)-(dimethyl-piperazin-1-yl)-methanone0.091 (400 MHz, DMSO-D6) d ppm 0.80–0.96(m, 3H)1.06(s, 3H) 1.80(d,J=6.57 Hz, 3H) 2.26–2.42(m, J=1.52 Hz, 2H) 2.61–2.85(m, J=1.77 Hz,3H)4.35–4.47(m, J=6.32 Hz, 1H) 6.06(s, 2H)6.16(q, J=6.57 Hz, 1H) 7.02(s,1H) 7.27–7.40(m, 3H) 7.40–7.49(m, J=8.72, 8.72 Hz, 2H)7.51–7.62(m,J=8.84, 5.05 Hz, 1H) 7.93(s, 1H) 535 19/20 I-552

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-3-fluoro-phenyl)-(dimethyl-piperazin-1-yl)-methanone0.2237 (400 MHz, DMSO-D6) d ppm 0.83–1.00(m, 3H)1.02–1.17(m, 3H) 1.78(d,3H) 2.70–2.98(m,6H) 4.36–4.50(m, 1H) 6.01–6.10(m, 2H)6.10–6.22(m, 1H)6.96–7.04 (m, 1H) 7.06–7.15(m, 1H) 7.16–7.23(m. 1H) 7.30–7.39(m,1H)7.40–7.49(m, 1H) 7.50–7.59(m, 1H)7.86–7.98(m, 1H) 535 19/20 I-553

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-3-methyl-phenyl)-(dimethyl-piperazin-1-yl)-methanone0.2593 (400 MHz, DMSO-D6) d ppm 0.88(s, 3H) 1.01(s, 3H) 1.77(d, J=6.57Hz, 3H) 1.96(s, 3H)2.31(s, 1H) 2.73(s, 3H) 3.50(s, 2H) 4.35(s,1H)5.89(s, 2H) 6.00(q, J=6.57 Hz, 1H) 6.60(s,1H) 7.01–7.12(m, J=7.83 Hz,1H) 7.12–7.28(m, 2H) 7.37–7.63(m, 3H) 531 19/20 I-554

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-methanone0.1407 (400 MHz, DMSO-D6) d ppm 1.00–1.31(m, 4H)1.87(d, J=6.82 Hz, 3H)3.37–3.40(m, 6H)3.55–3.65(m, 2H) 6.01–6.05(m, 2H) 6.21(q, J=6.57 Hz, 1H)7.07(d, J=1.77 Hz, 1H)7.45–7.55(m, 5H) 7.63(dd, J=8.84, 5.05 Hz,1H)7.92–7.98(m, 1H) 518 19 I-555

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-ethoxy-phenyl)-pyridin-2-ylamine22% (400 MHz, DMSO-D6) d ppm 1.36(t, J=6.82 Hz,3H) 1.95(d, J=6.57 Hz,3H) 4.08–4.16(m, 2H)5.91–5.95(m, 2H) 6.16(q, J=6.57 Hz, 1H) 7.08–7.13(m,2H) 7.19(d, J=7.83 Hz, 1H) 7.27(dd,J=7.58, 1.77 Hz, 1H) 7.40(t, J=8.59Hz, 1H)7.62(t, J=8.59 Hz, 1H) 7.73(dd, J=9.09, 5.05Hz, 1H) 7.84(d,J=1.77 Hz, 1H) 421 19 I-556

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,5-dimethoxy-phenyl)-pyridin-2-ylamine0.5746 (400 MHz, DMSO-D6) d ppm 1.82(d, J=6.57 Hz,3H) 3.57–3.58(m, 3H)3.74–3.75(m, 3H)5.82–5.86(m, 2H) 6.03(q, J=6.57 Hz, 1H) 6.72(d, J=3.28Hz, 1H) 6.84(dd, J=8.84, 3.03 Hz,1H) 6.89(d, J=1.77 Hz, 1H) 6.98(d,J=9.09 Hz,1H) 7.50(t, J=8.59 Hz, 1H) 7.61(dd, J=8.84, 4.80Hz, 1H)7.66(d, J=1.77 Hz, 1H) 4.37 19 I-557

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,4-dimethoxy-phenyl)-pyridin-2-ylamine0.2172 (400 MHz, DMSO-D6) d ppm 1.83(d, J=6.82 Hz,3H) 3.64–3.67(m, 3H)3.81–3.84(m, 3H)5.74–5.78(m, 2H), 6.03(q, J32 6.57 Hz, 1H) 6.59(dd,J=8.34, 2.27 Hz, 1H) 6.64(d, J=2.53 Hz, 1H)6.88(d, J=1.77 Hz, 1H)7.10(d, J=8.34 Hz, 1H)7.53(t, J=8.59 Hz, 1H) 7.58(d, J=1.77 Hz,1H)7.63(dd, J=8.84, 5.05 Hz, 1H) 437 19 I-558

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,6-dimethoxy-phenyl)-pyridin-2-ylamine2% (400 MHz, DMSO-D6) d ppm 1.81(d, J=6.82 Hz,3H) 3.58–3.59(m, 6H)5.68–5.69(m, 2H)5.96(q, J=6.82 Hz, 1H) 6.63(d, J=1.77 Hz, 1H)6.71(d,J=8.34 Hz, 2H) 7.26(t, J=8.34 Hz, 1H)7.42(d, J=1.52 Hz, 1H) 7.52(t,J=8.59 Hz, 1H)7.61(dd, J=8.84, 5.05 Hz, 1H) 437 19 I-559

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine4% (400 MHz, DMSO-D6) d ppm 1.78(d, J=6.57 Hz,3H) 5.91–5.99(m, 3H)6.59–6.60(m, 1H)7.26(d, J=7.58 Hz, 1H) 7.42–7.48(m, 2H) 7.50–7.58(m, 2H)7.65(t, J=7.33 Hz, 1H) 7.75(d,J=7.83 Hz, 1H) 445 19 I-560

5-(2-Chloro-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine24% (400 MHz, DMSO-D6) d ppm 1.79(d, J=6.82 Hz,3H) 5.96–6.03(m, 3H)6.75(d, J=1.77 Hz, 1H)7.27–7.38(m, 3H) 7.42–7.49(m, 2H) 7.52–7.57(m, 2H)411 19 I-561

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-trifluoromethoxy-phenyl)-pyridin-2-ylamine14% (400 MHz, DMSO-D6) d ppm 1.74(d, J=6.82 Hz,3H) 5.92–5.98(m, 3H)6.74(d, J=1.77 Hz, 1H)7.29–7.43(m, 5H) 7.50(dd, J=9.09, 5.05 Hz,1H)7.56(d, J=1.77 Hz, 1H) 461 19 I-562

1-(2-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-ethanone8% (400 MHz, DMSO-D6) d ppm 1.83(d, J=6.82 Hz,3H) 1.92–1.93(m, 3H)6.01–6.07(m, 3H)6.59(d, J=2.02 Hz, 1H) 7.26(d, J=7.83 Hz, 1H)7.45(t,J=7.33 Hz, 1H) 7.48–7.51(m, 1H) 7.52–7.58(m, 3H) 7.61(dd, J=8.84, 5.05Hz, 1H) 419 19 I-563

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-fluoro-phenyl)-pyridin-2-ylamine0.4322 (400 MHz, DMSO-D6) d ppm 1.71(d, J=6.57 Hz,3H) 5.88–5.90(m, 2H)5.96(q, J=6.82 Hz, 1H)6.76–6.78(m, 1H) 7.10–7.16(m, 2H) 7.19–7.28(m, 2H)7.36(t, J=8.59 Hz, 1H) 7.47(dd,J=8.84, 4.80 Hz, 1H) 7.60–7.63(m, 1H) 39519 I-564

(2-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanol21% (400 MHz, DMSO-D6) d ppm 1.79(d, J=6.57 Hz,3H) 4.20(t, J=5.05 Hz,2H) 5.03(t, J=5.56 Hz,1H) 5.82–5.83(m, 2H) 6.02(q, J=6.57 Hz, 1H)6.68(d,J=1.77 Hz, 1H) 7.01(dd, J=7.58, 1.52Hz, 1H) 7.25(dt, J=7.58, 1.52 Hz,1H) 7.31(dt,J=7.33, 1.26 Hz, 1H) 7.46(t, J=8.59 Hz, 1H)7.49–7.53(m, 2H)7.56(dd, J=8.84, 5.05 Hz, 1H) 407 19 I-565

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-o-tolyl-pyridin-2-ylamine25% (400 MHz, DMSO-D6) d ppm 1.65(d, J=6.57 Hz,3H) 1.80–1.80(m, 3H)5.67–5.69(m, 2H)5.86(q, J=6.57 Hz, 1H) 6.45(d, J=1.77 Hz,1H)6.86–6.90(m, 1H) 7.00–7.09(m, 3H) 7.29–7.35(m, 2H) 7.42(dd, J=8.84,5.05 Hz, 1H) 391 19 I-566

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-methoxy-phenyl)-pyridin-2-ylamine0.2779 (400 MHz, DMSO-D6) d ppm 1.84(d, J=6.57 Hz,3H) 3.65–3.66(m, 3H)5.83–5.84(m, 2H)6.04(q, J=6.57 Hz, 1H) 6.93(d, J=1.77 Hz, 1H)7.00(dt,J=7.33, 1.01 Hz, 1H) 7.08(d, J=7.83Hz, 1H) 7.19(dd, J=7.58, 1.77 Hz, 1H)7.28–7.34(m, 1H) 7.53(t, J=8.84 Hz, 1H) 7.61–7.66(m, 2H) 407 19 I-567

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,6-dimethyl-phenyl)-pyridin-2-ylamine0% (400 MHz, DMSO-D6) d ppm 1.57–1.58(m, 3H)1.79(d, J=6.82 Hz, 3H)1.97–1.98(m, 3H)5.73–5.75(m, 2H) 5.98(q, J=6.57 Hz, 1H) 6.41(d, J=1.77Hz, 1H) 6.99–7.11(m, 3H) 7.25(d,J=1.77 Hz, 1H) 7.44(t, J=8.59 Hz, 1H)7.54(dd,J=8.64, 5.05 Hz, 1H) 405 19 I-568

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-morpholin-4-yl-methanone0.0525 Anal. Calcd for C24 H22 Cl2 F N3 O3: C, 58.79;H, 4.52; N, 8.57.Found: C, 58.39; H, 4.72; N, 8.24. 490 20 I-569

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-chloro-phenyl)-((3R,5S)-dimethyl-piperazin-1-yl)-methanone0.0478 Anal. Calcd for C26 H26 Cl3 F N4 O2: C, 56.59;H, 4.75; N, 10.15.Found: C, 52.83; H, 5.16; N,8.79. 1.1 eq of H2O; 1.3 eq AcOH 551 19/20I-570

4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl)-2-methyl-phenyl)-((3R,5S)-dimethyl-piperazin-1-yl)-methanone0.225 Anal. Calcd for C27 H29 Cl2 F N4 O2: C, 61.02;H, 5.50; N, 10.54.Found: C, 55.99; H, 5.79; N,9.01. 1.2 eq of H2O; 1.5 eq of AcOH 53119/20 I-571

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-((2R,6S)-2,6-dimethyl-morpholin-4-ylmethyl)-phenyl]-pyridin-2-ylamine0.2204 (400 MHz, CHLOROFORM-D) d ppm 1.09(d,J=6.32 Hz, 6H) 1.80(d,J=6.82 Hz, 3H) 1.88–1.98(m, 2H) 2.78–2.90(m, 2H) 3.59–3.70(m,2H)3.86–3.95 (m, 2H) 5.12–5.16(m, 2H)6.06(q, J=6.57 Hz, 1H) 6.94–7.04(m,2H) 7.25(dd, J=8.84, 4.80 Hz, 1H) 7.28–7.34(m, 2H)7.36–7.44(m, 2H)7.77(d, J=1.52 Hz, 1H) 504 28 I-572

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-morpholin-4-ylmethyl-phenyl)-pyridin-2-ylamine0.0554 (400 MHz, CHLOROFORM-D) d ppm 1.80(d,J=6.57 Hz, 3H) 2.51–2.58(m,4H) 3.58–3.60(m, 2H) 3.75(t, J=4.55 Hz, 4H) 5.27–5.31(m, 2H)6.06(q,J=6.57 Hz, 1H) 6.95(d, J=1.52 Hz, 1H)7.00(t, J=8.08 Hz, 1H) 7.22–7.29(m,3H)7.33–7.37(m, 2H) 7.74(d, J=1.77 Hz, 1H) 476 28 I-573

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-dimethyl-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.64(d, J=6.57 Hz,3H) 2.08–2.10(m, 6H)5.65–5.68(m, 2H)5.93(q, J=6.57 Hz, 1H) 6.69–6.71(m, 2H) 6.75–6.78(m, 2H)7.28(t, J=8.59 Hz, 1H) 7.40(dd,J=9.09, 4.80 Hz, 1H) 7.62(d, J=1.77 Hz,1H) 405 19 I-574

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-m-tolyl-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.78(d, J=6.57 Hz,3H) 2.27–2.28(m, 3H)5.80–5.84(m, 2H)6.08(q, J=6.57 Hz, 1H) 6.88(d, J=1.77 Hz, 1H)7.02(d,J=7.33 Hz, 1H) 7.09–7.15(m, 2H) 7.21(t, J=7.58 Hz, 1H) 7.41(t, J=8.59Hz, 1H) 7.54(dd, J=9.09, 5.05 Hz, 1H) 7.77(d, J=1.77 Hz, 1H) 391 19I-575

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-dimethoxy-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.60(d, J=6.57 Hz,3H) 3.55(d, J=14.91 Hz, 6H)5.57–5.60(m, 2H)5.90(q, J=6.57 Hz, 1H) 6.63(d, J=2.02 Hz, 1H)6.65(d,J=1.77 Hz, 1H) 6.68–6.76(m, 2H)7.23(t, J=8.59 Hz, 1H) 7.36(dd, J=4.80,4.04Hz, 1H) 7.58(d, J=1.77 Hz, 1H) 437 19 I-576

5-Biphenyl-3-yl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.83(d, J=6.57 Hz,3H) 5.92–5.95(m, 2H) 6.16(q,J=6.57 Hz, 1H)7.01(d, J=1.52 Hz, 1H) 7.38–7.59(m, 9H) 7.69(d, J=7.33 Hz,2H) 7.93(d, J=1.52 Hz, 1H) 453 19 I-577

5-(3,5-Bis-trifluoromethyl-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.84(d, J=6.57 Hz,3H) 6.16–6.24(m, 3H) 7.03(d,J=1.77 Hz, 1H)7.45(t, J=8.59 Hz, 1H) 7.54(dd, J=9.09, 5.05Hz, 1H)7.92–7.95(m, 1H) 8.00–8.02(m, 2H)8.08(d, J=2.02 Hz, 1H) 513 19 I-578

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-dichloro-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.87(d, J=6.57 Hz,3H) 6.09–6.12(m, 2H) 6.22(q,J=8.57 Hz, 1H)7.04(d, J=1.77 Hz, 1H) 7.46–7.53(m, 2H) 7.62(dd, J=9.09,5.05 Hz, 1H) 7.66–7.70(m, 2H)7.96(d, J=2.02 Hz, 1H) 446 19 I-579

1-(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-ethanone(400 MHz, DMSO-D6) d ppm 1.76(d, J=6.57 Hz,3H) 2.54–2.55(m, 3H)5.90–5.94(m, 2H)6.10(q, J=6.57 Hz, 1H) 6.93(d, J=1.77 Hz, 1H)7.39(t,J=8.59 Hz, 1H) 7.46(t, J=7.83 Hz, 1H)7.51(dd, J=9.09, 5.05 Hz, 1H)7.63(d, J=8.34Hz, 1H) 7.76(d, J=7.83 Hz, 1H) 7.81–7.83(m,1H) 7.85(d,J=2.02 Hz, 1H) 419 19 I-580

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-difluoro-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.82(d, J=6.57 Hz,3H) 6.06–6.10(m, 2H) 6.18(q,J=6.57 Hz, 1H)7.01(d, J=1.77 Hz, 1H) 7.06–7.19(m, 3H) 7.45(t, J=8.84 Hz,1H) 7.58(dd, J=9.09, 5.05 Hz, 1H)7.95(d, J=2.02 Hz, 1H) 413 19 I-581

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,5-dichloro-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.90(d, J=6.82 Hz,3H) 6.10(q, J=6.57 Hz, 1H)6.17–6.19(m, 2H)6.84(d, J=1.77 Hz, 1H) 7.44–7.51(m, 2H) 7.56(t, J=8.59Hz, 1H) 7.59–7.70(m, 3H) 446 19 I-582

(4-{6-Amino-5-[1-(2,6-dichloro-4-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanonePassed CHN 1.0 eq AcOH 567 18/20 I-583

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-ethoxy-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.35(t, J=6.82 Hz,3H) 1.82(d, J=6.57 Hz, 3H)3.99–4.09(m, 2H)5.88–5.91(m, 2H) 6.13(q, J=6.57 Hz, 1H) 6.80(dd, J=8.08,2.27 Hz, 1H) 6.84(t, J=2.02 Hz, 1H)6.92(d, J=1.77 Hz, 1H) 6.96(d, J=7.58Hz,1H) 7.26(t, J=7.83 Hz, 1H) 7.46(t, J=8.59 Hz, 1H)7.57(dd, J=8.84,5.05 Hz, 1H) 7.83(d,J=1.77 Hz, 1H) 421 19 I-584

5-(3-Chloro-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.87(d, J=6.57 Hz,3H) 6.03–6.06(m, 2H)6.18–6.24(m, 1H)7.02(d, J=2.02 Hz, 1H) 7.35(td, J=6.82, 1.77Hz, 1H)7.41–7.53(m, 4H) 7.62(dd, J=8.84,5.05 Hz, 1H) 7.93(d, J=2.02 Hz, 1H) 41119 I-585

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-fluoro-3-methyl-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.58(d, J=6.57 Hz,3H) 2.01–2.02(m, 3H)5.62–5.64(m, 2H)5.89(q, J=6.82 Hz, 1H) 6.68(d, J=1.77 Hz, 1H)6.90(t,J=8.84 Hz, 1H) 6.96–7.04(m, 2H) 7.22(t, J=8.59 Hz, 1H) 7.34(dd, J=9.09,5.05 Hz, 1H)7.56(d, J=1.77 Hz, 1H) 409 19 I-586

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.84(d, J=6.57 Hz,3H) 6.05–6.07(m, 2H)6.14–6.21(m, 1H)6.99(d, J=1.77 Hz, 1H) 7.46(t, J=8.59 Hz, 1H)7.56(dd,J=8.84, 5.05 Hz, 1H) 7.59–7.65(m, 3H)7.76–7.80(m, 1H) 7.95(d, J=1.77 Hz,1H) 445 19 I-587

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-fluoro-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.82(d, J=6.57 Hz,3H) 5.98–6.00(m, 2H)6.13–6.20(m, 1H)6.99(d, J=1.77 Hz, 1H) 7.05–7.11(m, 1H) 7.21–7.27(m, 2H)7.39–7.49(m, 2H) 7.59(dd,J=9.09, 5.05 Hz, 1H) 7.90(d, J=2.02 Hz, 1H) 39519 I-588

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-trifluoromethoxy-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.60(d, J=6.57 Hz,3H) 5.80–5.84(m, 2H)5.90–5.98(m, 1H)6.73(d, J=2.02 Hz, 1H) 7.00–7.07(m, 2H) 7.20–7.30(m, 3H)7.34(dd, J=8.84, 4.80 Hz, 1H)7.68(d, J=1.77 Hz, 1H) 461 19 I-589

5-Benzo[1,3]dioxol-5-yl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.82(d, J=6.57 Hz,3H) 5.81–5.83(m, 2H)6.03–6.04(m, 2H)6.10–6.17(m, 1H) 6.83–6.96(m, 4H) 7.46(t,J=8.84 Hz, 1H)7.58(dd, J=9.09, 5.05 Hz, 1H)7.76(d, J=2.02 Hz, 1H) 421 19 I-590

3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenol(400 MHz, DMSO-D6) d ppm 1.95(d, J=6.82 Hz,3H) 5.98–6.00(m, 2H)6.22–6.28(m, 1H)6.78–6.81(m, 1H) 6.89–6.93(m, 2H) 7.04(d,J=1.77 Hz, 1H)7.29(t, J=8.08 Hz, 1H) 7.58(t,J=9.09, 8.59 Hz, 1H) 7.71(dd, J=8.84, 4.80Hz,1H) 7.89(d, J=1.77 Hz, 1H) 9.55–9.57(m, 1H) 393 19 I-591

(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanol(400 MHz, DMSO-D6) d ppm 1.83(d, J=6.57 Hz,3H) 4.52(d, J=5.31 Hz, 2H)5.16–5.22(m, 1H)5.88–5.90(m, 2H) 6.11–6.17(m, 1H) 6.96(d,J=1.52 Hz, 1H)7.20–7.28(m, 2H) 7.31–7.36(m, 2H) 7.46(t, J=8.84 Hz, 1H) 7.58(dd,J=9.09,5.05 Hz, 1H) 7.83(d, J=1.77 Hz, 1H) 407 19 I-592

3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzonitrile(400 MHz, DMSO-D6) d ppm 1.88(d, J=8.57 Hz,3H) 6.10–6.12(m, 2H) 6.24(q,J=6.57 Hz, 1H)7.12(d, J=1.77 Hz, 1H) 7.51(t, J=8.59 Hz, 1H)7.60–7.68(m,2H) 7.77(d, J=7.83 Hz, 1H) 7.81(d, J=8.08 Hz, 1H) 7.94–7.96(m, 1H)8.00(d,J=1.77 Hz, 1H) 402 19 I-593

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-methoxy-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.83(d, J=6.57 Hz,3H) 3.79–3.80(m, 3H)5.91–5.92(m, 2H)6.11–6.18(m, 1H) 6.81–6.84(m, 1H) 6.86–6.89(m, 1H)6.93(d, J=1.52 Hz, 1H) 6.97–7.01(m, 1H) 7.29(t, J=8.34, 7.83 Hz, 1H)7.46(t,J=8.84 Hz, 1H) 7.59(dd, J=9.09, 5.05 Hz, 1H)7.85(d, J=1.77 Hz,1H) 407 19 I-594

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-dichloro-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.83(d, J=6.57 Hz,3H) 6.10–6.12(m, 2H)6.16–6.22(m, 1H)7.00(d, J=1.77 Hz, 1H) 7.44–7.49(m, 4H) 7.58(dd, J=9.09,5.31 Hz, 1H) 7.95(d, J=2.02 Hz, 1H) 446 19 I-595

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,5-dimethyl-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.80(d, J=6.82 Hz,3H) 1.90–1.93(m, 3H)2.24–2.27(m, 3H)5.81–5.83(m, 2H) 6.00(q, J=6.82, 6.32 Hz, 1H)6.57(d,J=1.77 Hz, 1H) 6.79–6.82(m, 1H)6.98–7.03(m, 1H) 7.10(d, J=7.83 Hz, 1H)7.45–7.52(m, 2H) 7.58(dd, J=8.84, 5.05 Hz, 1H) 405 19 I-596

5-(5-Chloro-2-methoxy-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.79(d, J=6.57 Hz,3H) 3.61–3.63(m, 3H)5.89–5.91(m, 2H)5.97–6.03(m, 1H) 6.86(d, J=1.77 Hz, 1H) 7.06(d, J=8.84Hz, 1H) 7.15(d, J=2.78 Hz, 1H) 7.29(dd, J=8.84, 2.53 Hz, 1H) 7.49(t,J=8.59 Hz, 1H)7.59(dd, J=9.09, 5.31 Hz, 1H) 7.63(d,J=1.77 Hz, 1H) 441 19I-597

5-(3-Chloro-4-fluoro-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.83(d, J=6.57 Hz,3H) 5.98–6.00(m, 2H)6.14–6.20(m, 1H)6.98(d, J=1.77 Hz, 1H) 7.42–7.45(m, 2H) 7.47(d, J=8.59Hz, 1H) 7.55–7.60(m, 2H) 7.87(d, J=2.02 Hz, 1H) 429 19 I-598

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(5-fluoro-2-methoxy-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.79(d, J=6.57 Hz,3H) 3.59–3.60(m, 3H)5.88–5.91(m, 2H) 6.00(q, J=6.82 Hz, 1H) 6.90(d, J=1.77 Hz,1H)6.99–7.10(m, 3H) 7.48(t, J=8.84 Hz, 1H) 7.59(dd, J=9.09, 5.31 Hz, 1H)7.64(d, J=2.02 Hz, 1H) 425 19 I-599

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-isopropyl-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.20–1.25(m, 6H)1.83(d, J=6.57 Hz, 3H)2.86–2.94(m, 1H)5.88–5.91(m, 2H) 6.13(q, J=6.32 Hz, 1H) 6.89(d, J=1.77Hz, 1H) 7.11–7.15(m, 2H) 7.23–7.31(m, 2H) 7.47(t, J=8.59 Hz, 1H)7.58(dd,J=8.84, 4.80 Hz, 1H) 7.83(d, J=2.02 Hz, 1H) 419 19 I-600

5-(3-Chloro-4-trifluoro-methyl-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.83(d, J=6.57 Hz,3H) 6.11–6.13(m, 2H) 6.17(q,J=6.57 Hz, 1H)6.99(d, J=1.77 Hz, 1H) 7.46(t, J=8.84 Hz, 1H)7.56(dd,J=9.09, 5.05 Hz, 1H) 7.68(d, J=1.77Hz, 1H) 7.72(d, J=8.59 Hz, 1H)7.80(dd,J=8.34, 1.77 Hz, 1H) 7.95(d, J=2.02 Hz, 1H) 478.90 19 I-601

4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzonitrile(400 MHz, DMSO-D6) d ppm 1.83(d, J=6.57 Hz,3H) 6.13–6.22(m, 3H) 7.06(d,J=1.77 Hz, 1H)7.45(t, J=8.59 Hz, 1H) 7.57(dd, J=9.09, 5.05Hz, 1H)7.63(d, J=8.59 Hz, 2H) 7.84(d, J=8.59Hz, 2H) 7.97(d, J=1.77 Hz, 1H) 40219 I-602

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-difluoro-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 1.82(d, J=6.82 Hz,3H) 5.96–6.00(m, 2H) 6.17(q,J=6.57 Hz, 1H)6.99(d, J=1.77 Hz, 1H) 7.22–7.27(m, 1H) 7.41–7.52(m, 3H)7.58(dd, J=9.09, 5.05 Hz, 1H)7.87(d, J=2.02 Hz, 1H) 413 19 I-603

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-[1,4]-diazepan-1-yl)-methanone0.0095 (400 MHz, DMSO-D6) d ppm 1.73(m, 1H) 1.80(d, J=6.82 Hz, 3H)1.84(m, 1H) 2.26 (d,J=21.98 Hz, 2H) 2.53(m, 2H) 2.63(m, 2H) 3.40(m, 2H)3.60(m, 2H) 5.95(s, 2H) 6.14(d,J=6.57 Hz, 1H) 6.99(s, 1H) 7.36(d, J=7.58Hz,2H) 7.44(m, 3H) 7.57(dd, J=8.97, 4.93 Hz, 1H)7.86(d, J=1.77 Hz, 1H)517 20 I-604

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-[1,4]diazepan-1-yl-methanone0.031 (400 MHz, DMSO-D6) d ppm 1.81(t, J=6.19 Hz,3H) 1.90(m, 2H) 2.96(m,2H) 3.10(d, J=36.88Hz, 2H) 3.45(m, 2H) 3.7(m, 2H) 5.96(s, 2H)6.14(q,J=6.82 Hz, 1H) 6.99(d, J=1.52 Hz, 1H)7.44(m, 5H) 7.56(dd, J=8.97, 4.93Hz, 1H)7.87(d, J=1.77 Hz, 1H) 503 20/21 I-605

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-piperazin-1-yl-methanone0.0475 (400 MHz, DMSO-D6) d ppm 1.80(d, J=6.57 Hz,3H) 2.72(m, 4H)3.36(m, 2H) 3.52(m, 2H) 5.96(s, 2H) 6.14(q, J=6.74 Hz, 1H) 6.99(d,J=1.77Hz, 1H) 7.37(m, 2H) 7.44(m, 3H) 7.57(dd,J=8.97, 4.93 Hz, 1H)7.87(d, J=1.77 Hz, 1H) 489 20/21 I-606

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-vinyl-pyridin-2-ylamine0.655 (400 MHz, CHLOROFORM-D) d ppm 1.83(d,J=6.57 Hz, 3H) 4.84(s, 2H)5.03(d, J=11.12Hz, 1H) 5.38(d, J=17.43 Hz, 1H) 6.06(q,J=6.82 Hz, 1H)6.49(dd, J=17.68, 10.86 Hz,1H) 6.90(d, J=1.77 Hz, 1H) 7.04(dd,J=8.84,7.83 Hz, 1H) 7.29(dd, J=8.84, 4.80 Hz, 1H)7.55(d, J=1.77 Hz, 1H)327 19 I-607

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,4S)-3,4-dihydroxy-pyrrolidin-1-yl)-methanone0.058 (400 MHz, DMSO-D6) d ppm 1.81(d, J=6.82 Hz,3H) 3.28(m, 2H) 3.54(m,2H) 3.97(d, J=4.04Hz, 2H) 4.08(d, J=4.29 Hz, 2H) 5.10(br, 2H)5.98(d, 2H)7.00(d, J=1.77 Hz, 1H) 7.45(m,3H) 7.48(m, 2H) 7.57(dd, J=8.97, 4.93 Hz,1H)7.88(d, J=1.77 Hz, 1H) 506 20/21 I-608

5-[(1-Benzyl-pyrrolidin-3-ylamino)-methyl]-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine0% (400 MHz, DMSO-D6) d ppm 1.34(m, 1H) 1.74(d, J=5.94 Hz, 3H) 1.78(m,1H) 2.08(m, 1H)2.40(m, 2H) 2.54(m, 1H) 2.89(m, 1H) 3.33(s,2H) 3.49(s,2H) 5.52(s, 2H) 5.94(q, J=6.57Hz, 1H) 6.68(s, 1H) 7.27(m, 5H) 7.36(m,1H)7.39(m, 1H) 7.48(m, 1H) 489 23 I-609

4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-azetidin-3-yl-benzamide0.045 (400 MHz, DMSO-D6) d ppm 1.80(d, J=6.57 Hz,3H) 2.87(m, 1H) 3.43(m,1H) 3.81(m, 2H)4.74(m, 1H) 6.00(s, 2H) 6.13(q, J=6.48 Hz,1H) 6.96(dd,J=6.57, 1.77 Hz, 1H) 7.45(m, 3H)7.54 (dd, J=8.97, 4.93 Hz, 1H) 7.87(m,3H) 475 20/21 I-610

4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N,N-dimethyl-benzenesulfonamide0.069 (400 MHz, CHLOROFORM-D) d ppm 1.87(d,J=6.82 Hz, 3H) 2.72(s, 6H)4.99(s, 2H) 6.12 (q,J=6.57 Hz, 1H) 6.99(d, J=1.77 Hz, 1H) 7.07(m,1H)7.32(dd, J=8.84, 4.80 Hz, 1H) 7.50(m, 2H)7.76(d, J=8.59 Hz, 2H) 7.91(d,J=1.77 Hz, 1H) 484 29 I-611

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(6-methoxy-1H-benzoimidazol-2-yl)-pyridin-2-ylamine(400 MHz, MeOD) d ppm 1.72(d, J=6.57 Hz,3H) 3.69(s, 3H) 4.78(s, 2H)6.13(q, J=6.57 Hz,1H) 6.71(dd, J=8.84, 2.27 Hz, 1H) 6.88(d,J=2.02 Hz,1H) 7.04(m, 1H) 7.26(m, 2H) 7.40(d, J=1.77 Hz, 1H) 8.03(d, J=2.02 Hz,1H) 447 24 I-612

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(6-methoxy-1-methyl-1H-benzoimidazol-2-yl)-pyridin-2-ylamine(400 MHz, MeOD) d ppm 1.78(d, J=6.57 Hz,3H) 3.51(s, 3H) 3.75(s, 3H)6.10(q, J=6.32 Hz,1H) 6.90(m, 1H) 6.92(m, 1H) 7.13(m, 1H)7.35(m, 2H)7.80(d, J=7.33 Hz, 1H) 461 24 I-613

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(4-methyl-[1,4]-diazepane-1-sulfonyl)-phenyl]-pyridin-2-ylamine(400 MHz, MeOD) d ppm 1.83(m, 2H) 1.87(d,J=6.57 Hz, 3H) 2.66(m, 4H)3.35(m, 2H) 3.40(m, 2H) 6.20(q, J=6.65 Hz, 1H) 7.02(d, J=1.77Hz, 1H)7.20(t, J=8.59 Hz, 1H) 7.43(dd,J=8.97, 4.93 Hz, 1H) 7.54(d, J=8.34 Hz,2H)7.77(d, J=8.59 Hz, 2H) 7.81(d, J=1.26 Hz, 1H) 553 29 I-614

6-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1-methyl-1H-indazole-3-carboxylicacid amide (400 MHz, DMSO-D6) d ppm 1.82(d, J=6.57 Hz,3H) 3.92(s, 3H)5.96(s, 2H) 6.17(q, J=6.48Hz, 1H) 7.03(d, J=1.77 Hz, 1H) 7.35(dd,J=8.59,1.26 Hz, 1H) 7.44(t, J=8.72 Hz, 1H)7.56(m, 2H) 7.91(d, J=2.02 Hz, 1H)8.03(d,J=8.59 Hz, 1H) 475 26 I-615

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-methyl-1H-pyrazol-4-yl)-pyridin-2-ylamine(400 MHz, CHLOROFORM-D) d ppm 1.84(d,J=6.82 Hz, 3H) 3.89(s, 3H) 4.76(s,2H) 6.05(q, J=6.57 Hz, 1H) 6.84(d, J=1.77 Hz, 1H) 7.03(m, 1H) 7.28(dd,J=8.97, 4.93 Hz, 1H) 7.40(s,1H) 7.53(s, 1H) 7.74(d, J=1.77 Hz, 1H) 38119 I-616

(4-{6-Amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone3% (400 MHz, DMSO-D6) d ppm 9.29(d, J=9.60 Hz,1H) 8.63(d, J=10.86 Hz,1H) 7.84–7.94 (m,2H) 7.72(t, J=7.96 Hz, 3H) 7.47–7.57(m, 6H)7.35(s, 1H)5.97–6.05(m, 1H) 3.37(s, 2H) 1.69(d, J=6.06 Hz, 3H) 1.15(s, 5H) 1.06(s,1H) 500 33 I-617

(4-{6-Amino-5-[1-(3-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone2% (400 MHz, DMSO-D6) d ppm 9.26(s, 2H) 8.64(s, 2H) 7.93(s, 2H) 7.84(d,J=1.52 Hz, 2H)7.81(d, J=7.58 Hz, 2H) 7.66(s, 2H) 7.60(d,J=8.34 Hz, 5H)7.53–7.59(m, 2H) 7.46(d,J=8.34 Hz, 4H) 6.01(q, J=6.32 Hz, 2H) 3.32(s,4H)3.03(s, 1H) 2.75(s, 1H) 1.61(d, J=6.32Hz, 5H) 1.13(s, 7H) 500 32 I-618

7-[4-(3,5-Dimethyl-piperazine-1-carbonyl)-phenyl]-2-phenyl-4H-pyrido[3,2-b][1,4]oxazin-3-one0% (400 MHz, DMSO-D6) d ppm 8.53(s, 2H) 8.33(d, J=2.02 Hz, 2H) 7.84(d,J=2.02 Hz, 2H) 7.80(d, J=8.34 Hz, 5H) 7.36–7.42(m, 12H) 5.93(s,2H)4.55(s, 1H) 3.73(s, 3H) 3.40(s, 6H) 1.19(s, 10H) 444 32 I-619

{4-[6-Amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone16% (400 MHz, DMSO-D6) d ppm 7.97(d, J=1.77 Hz,1H) 7.79(s, 1H)7.66–7.74(m, 3H) 7.48 (d,J=1.77 Hz, 2H) 7.41(d, J=8.34 Hz, 2H)7.24(s,1H) 5.91(s, 1H) 5.40(s, 2H) 3.61(s, 1H) 2.61–2.70(m, 3H) 2.33(s,1H) 2.17(s, 1H) 1.95–2.06(m, 1H) 1.47(s, 1H) 1.23(s, 7H) 1.00(s,3H)0.80–0.92(m, 6H) 504 32 I-620

{4-[6-Amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone5% (400 MHz, DMSO-D6) d ppm 8.02(s, 1H) 7.96(s, 1H) 7.85(d, J=8.34 Hz,2H) 7.51–7.62(m,3H) 7.23(t, J=8.08 Hz, 2H) 5.43(s, 2H) 4.09(s,1H)3.37(s, 1H) 1.40(s, 9H) 1.14(d, J=2.27 Hz,3H) 1.08(d, J=16.42 Hz, 3H)454 34 I-621

[4-(6-Amino-5-benzyloxy-pyridin-3-yl)-phenyl]-(3,5-dimethyl-piperazin-1-yl)-methanone6% (400 MHz, DMSO-D6) d ppm 9.35(s, 1H) 8.70(s, 1H) 7.96(s, 2H) 7.78(d,J=8.59 Hz, 4H)7.55(d, J=8.08 Hz, 5H) 7.42(t, J=7.20 Hz, 2H)7.35(t,J=7.33 Hz, 1H) 5.40(s, 2H) 3.39(s, 2H)3.16(s, 1H) 1.20(s, 4H) 418 34I-622

(4-{6-Amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-ethyl-piperazin-1-yl)-methanone0.375 (400 MHz, DMSO-D6) d ppm 7.95(d, J=1.77 Hz,1H) 7.57(d, J=8.34 Hz,2H) 7.52(s, 1H) 7.45(d, J=8.08 Hz, 3H) 7.25(d, J=1.77 Hz, 1H) 6.11(s,1H) 5.95(s, 2H) 3.62(s, 1H) 3.49(s, 1H)2.44(s, 2H) 2.41(d, J=7.07 Hz,4H) 1.85(d,J=6.32 Hz, 3H) 1.06(t, J=7.20 Hz, 3H) 502  4 I-623

[4-(6-Amino-5-benzyloxy-pyridin-3-yl)-phenyl]-(4-ethyl-piperazin-1-yl)-methanone7% (400 MHz, DMSO-D6) d ppm 7.91(d, J=2.02 Hz,1H) 7.65(d, J=8.34 Hz, 2H)7.53(d, J=7.33 Hz,2H) 7.44(d, J=1.77 Hz, 1H) 7.37–7.42(m, 3H)7.32(t,J=7.33 Hz, 1H) 5.94(s, 2H) 5.25(s, 2H)3.60(s, 1H) 3.38(s, 1H) 2.302.41(m, 5H)0.99(t, J=7.20 Hz, 3H) 418 34 I-624

{4-[6-Amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone0% (400 MHz, DMSO-D6) d ppm 9.40(s, 1H) 8.77(s, 1H) 7.98(d, J=1.52 Hz,1H) 7.77–7.88(m,4H) 7.57(d, J=8.34 Hz, 2H) 7.53(d, J=7.33 Hz,1H)7.21–7.31(m, 3H) 5.37(s, 2H) 3.39(s, 2H)2.37(s, 3H) 1.20(s, 4H) 432 34I-625

3-{2-Amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzoicacid methyl ester 6% (400 MHz, DMSO-D6) d ppm 9.78(s, 1H) 8.12(s, 1H)7.92–7.98(m, 2H) 7.88(d, J=7.58 Hz,1H) 7.74–7.83(m, 3H) 7.59(t, J=7.71Hz, 2H)7.48(d, J=8.34 Hz, 2H) 5.47(s, 2H) 3.86(s,3H) 3.50(s, 2H) 3.41(s,1H) 3.10(s, 2H) 2.00(s, 3H) 1.85(s, 2H) 1.53(s, 2H) 516  6 I-626

3-{2-Amino-5-[4-(3,5-dimethyl-piperazine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzoicacidmethyl ester 0% (400 MHz, DMSO-D6) d ppm 9.31(s, 2H) 8.67(s, 2H) 8.12(s,2H) 7.92–7.99(m, 4H) 7.88(d,J=7.83 Hz, 2H) 7.75–7.84(m, 6H) 7.53–7.63(m,6H) 5.48(s, 4H) 3.81–3.91(m, 6H) 3.39(s, 4H) 3.13(s, 1H) 1.20(s, 7H) 47634 I-627

{4-[6-Amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone6% (400 MHz, DMSO-D6) d ppm 9.91(s, 1H) 7.95(d, J=1.52 Hz, 1H) 7.85(s,1H) 7.80(d, J=8.34Hz, 2H) 7.53(d, J=7.07 Hz, 1H) 7.49(d, J=8.34Hz, 2H)7.21–7.31(m, 3H) 5.36(s, 2H) 4.56(s, 1H) 3.68(s, 1H) 3.51(s, 2H) 3.41(s,1H)3.10(s, 3H) 2.82(s, 1H) 2.37(s, 3H) 1.99(s,3H) 1.79–1.90(m, 2H)1.56(s, 2H) 472  6 I-628

[4-(6-Amino-5-cyclo-hexylmethoxy-pyridin-3-yl)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone7% (400 MHz, DMSO-D6) d ppm 7.90(d, J=1.52 Hz,1H) 7.79(d, J=8.34 Hz, 3H)7.66(s, 1H) 7.44–7.55(m, 2H) 4.03(d, J=6.06 Hz, 2H) 3.83(s,1H) 3.67(s,1H) 3.51(s, 2H) 3.39(s, 1H) 3.09(s, 2H) 2.82(s, 1H) 2.14(s, 2H) 1.99(s,3H)1.79–1.91(m, 5H) 1.64–1.76(m, 3H) 1.54(s,2H) 1.20–1.30(m, 2H) 1.07(d,J=11.62 Hz, 2H) 464  6 I-629

4-(1-{2-Amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-[2-(3-hydroxy-phenyl)-ethyl]-benzamide7% (400 MHz, DMSO-D6) d ppm 9.76(s, 1H) 8.51(t, J=5.56 Hz, 1H) 7.86(d,J=1.52 Hz, 2H) 7.79(d, J=8.34 Hz, 2H) 7.63(dd, J=14.40, 8.34 Hz,5H)7.45(d, J=8.34 Hz, 2H) 7.04(t, J=7.96 Hz,1H) 6.55–6.65(m, 3H) 6.00(d,J=6.32 Hz, 1H)3.49(s, 2H) 3.34–3.45(m, 3H) 3.09(s, 3H)2.75(s, 1H)2.65–2.74(m, 2H) 2.13(s, 1H)1.99(s, 3H) 1.78–1.89(m, 2H) 1.65(d,J=6.32Hz, 3H) 1.52(s, 2H) 635  6 I-630

4-(1-{2-Amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-[2-(2,6-dichloro-phenyl)-ethyl]-benzamide3% (400 MHz, DMSO-D6) d ppm 9.80(s, 1H) 8.62(t, J=5.81 Hz, 1H) 7.85(d,J=1.26 Hz, 1H) 7.78(d, J=8.34 Hz, 3H) 7.62(dd, J=12.63, 8.34 Hz,5H)7.39–7.49(m, 4H) 7.21–7.30(m, 1H) 5.98(d, J=6.32 Hz, 1H) 3.65(s, 1H)3.40–3.51(m,J=6.63, 6.63, 6.63, 6.63 Hz, 4H) 3.03–3.15(m,5H) 2.82(s, 1H)2.13(s, 1H) 1.98(s, 3H) 1.78–1.89(m, 2H) 1.65(d, J=6.06 Hz, 3H) 1.53(s,2H) 688  6 I-631

4-(1-{2-Amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-(1-benzyl-piperidin-4-yl)-benzamide3% (400 MHz, DMSO-D6) d ppm 7.75–7.82(m, 2H)7.56–7.67(m, 4H)7.39–7.49(m, 6H) 4.27 (d,J=4.80 Hz, 2H) 3.92(s, 1H) 3.49(s, 2H) 3.37(s,2H) 3.07(s, 3H) 2.12(s, 1H) 1.92–2.04(m,4H) 1.79–1.91(m, 2H) 1.71(d,J=11.87 Hz,1H) 1.59–1.68(m, 3H) 1.51(s, 2H) 688  4 I-632

4-(1-{2-Amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide0% (400 MHz, DMSO-D6) d ppm 8.39(s, 1H) 7.77–7.85(m, 3H) 7.61(t, J=8.08Hz, 6H) 7.43 (d,J=8.34 Hz, 2H) 5.96(s, 1H) 3.69(s, 2H) 3.49(s, 3H)3.39(s, 2H) 3.30(t, J=6.95 Hz, 3H) 3.14–3.22(m, 4H) 3.09(s, 3H) 2.18(t,J=8.08 Hz,2H) 2.00(s, 3H) 1.86(ddd, J=15.28, 7.58, 7.45Hz, 4H) 1.65(t,J=6.06 Hz, 5H) 1.52(s, 2H) 640  6 I-633

(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-ethyl-piperizin-1-yl)-methanone0.0472 (400 MHz, DMSO-D6) d ppm 9.85(s, 1H) 7.91(d, J=1.77 Hz, 1H)7.58(dd, J=8.97, 4.93 Hz,1H) 7.50–7.55(m, 4H) 7.44–7.50(m, 1H) 7.13(d,J=1.52 Hz, 1H) 6.27(q, J=6.57 Hz, 1H) 3.48(s, 2H) 3.15(q, J=7.07 Hz, 3H)3.06(s, 2H)1.84(d, J=6.57 Hz, 3H) 1.22(t, J=7.33 Hz, 3H) 518  6 I-634

{4-[6-Amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone10% (400 MHz, DMSO-D6) d ppm 9.29(s, 2H) 8.66(s,2H) 7.91–8.00(m, 5H)7.85(d, J=6.82 Hz, 5H)7.54–7.61(m, 10H) 7.48–7.53(m, 3H) 5.48(s,5H)4.61(s, 1H) 1.21(d, J=4.55 Hz, 9H) 1.15(s, 5H) 486 34 I-635

(6-Amino-3-aza-bicyclo[3.1.0]hex-3-yl)-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanone0.0554 (400 MHz, DMSO-D6) d ppm 8.14(d, J=3.54 Hz,3H) 7.87(s, 1H)7.58(dd, J=8.97, 4.93 Hz, 1H)7.44–7.53(m, 5H) 7.12(s, 1H) 6.25(s,1H)3.95(d, J=11.87 Hz, 1H) 3.69(s, 2H) 1.96(d,J=13.39 Hz, 2H) 1.84(d,J=6.57 Hz, 3H) 502 35 I-636

5-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-6′-(2-morpholin-4-yl-ethoxy)-[3,3′]bipyridinyl-6-ylamine0.109 (400 MHz, DMSO-D6) d ppm 8.20(d, J=2.27 Hz,1H) 7.83(d, J=1.77 Hz,1H) 7.79(dd, J=8.59,2.53 Hz, 1H) 7.61(dd, J=8.97, 4.93 Hz, 1H)7.49(t,J=8.84 Hz, 1H) 6.98(d, J=1.77 Hz, 1H)6.88(d, J=8.59 Hz, 1H) 6.18(q,J=6.82 Hz, 1H)5.92(s, 2H) 4.41(t, J=5.81 Hz, 2H) 3.61(m,4H) 2.72(t,J=5.81 Hz, 2H) 2.47–2.52(m, 4H)1.85(d, J=6.57 Hz, 3H) 507 36 I-637

6′-Amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-1-(2-pyrrolidin-1-yl-ethyl)-1H-[3,3′]-bipyridinyl-6-one0.692 (400 MHz, DMSO-D6) d ppm 7.42–7.52(m, 2H)7.25–7.35(m, 2H) 7.22(t,J=8.72 Hz, 1H) 6.64(d, J=1.52 Hz, 1H) 6.19(d, J=9.35 Hz, 1H) 5.89(q,J=6.74 Hz, 1H) 5.58(s, 2H) 3.72–3.84(m,2H) 2.42–2.53(m, 2H) 1.57(d,J=6.57 Hz, 3H)1.39–1.50(m, 4H) 491 35 I-638

5-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-6′-(2-pyrrolidin-1-yl-ethoxy)-[3,3′]bipyridinyl-6-ylamine0.094 (400 MHz, DMSO-D6) d ppm 7.98(d, J=2.53 Hz,1H) 7.62(d, J=2.02 Hz,1H) 7.57(dd, J=8.59,2.53 Hz, 1H) 7.40(dd, J=8.97, 4.93 Hz, 1H)7.27(t,J=8.72 Hz, 1H) 6.77(d, J=1.77 Hz, 1H)6.66(d, J=8.59 Hz, 1H) 5.97(q,J=6.57 Hz, 1H)5.70(s, 2H) 4.17(t, J=5.81 Hz, 2H) 2.56–2.65(m, 2H)1.63(d, J=6.82 Hz, 3H) 1.46–1.54(m,4H) 0.97–1.09(m, 1H) 491 35 I-639

6′-Amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-[3,3′]bipyridinyl-6-one0.513 (400 MHz, DMSO-D6) d ppm 7.71(dd, J=9.60,1.77 Hz, 2H) 7.46–7.56(m,2H) 7.42(t, J=8.72Hz, 1H) 6.84(s, 1H) 6.39(d, J=9.35 Hz, 1H)6.10(q,J=6.57 Hz, 1H) 5.79(s, 2H) 3.98–4.08(m, 4H) 3.81–3.92(m, 2H)2.85–2.92(m, 2H)2.14–2.18(m, 7H) 1.93–2.05(m, 5H) 1.84–1.89(m, 2H)1.76–1.82(m, 4H) 1.52–1.63(m,6H) 1.26–1.38(m, 2H) 1.08–1.18(m, 6H) 505 3 I-640

(4-{6-Amino-5-[1-(2,4,6-trimethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone(400 MHz, MeOD) d ppm 7.62(d, J=1.52 Hz,1H) 7.25–7.31(m, 2H)7.19–7.25(m, 2H) 6.73(s, 2H) 6.65(d, J=1.77 Hz, 1H) 5.65(q, J=6.57Hz,1H) 4.46–4.57(m, 1H) 3.61–3.73(m, 1H)2.96–3.07(m, 1H) 2.73–2.84(m, 1H)2.50–2.59(m, 4H) 2.23–2.31(m, 7H) 2.10(s, 3H) 1.92–2.04(m, 1H)1.77–1.88(m, 1H) 1.69–1.76(m, 4H)1.66(d, J=6.82 Hz, 3H) 1.29–1.40(m, 2H)513  6 I-641

(4-{6-Amino-5-[1-(2-chloro-6-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone(400 MHz, MeOD) d ppm 7.66(d, J=2.02 Hz, 1H)7.28–7.39(m, 4H)7.12–7.23(m, 2H) 7.07(d, J=1.77 Hz, 1H) 6.92–7.02(m, 1H) 5.97(q,J=6.06Hz, 1H) 4.44–4.56(m, 1H) 3.62–3.74(m, 1H) 2.96–3.08(m, 1H) 2.72–2.84(m,1H)2.48–2.59(m, 4H) 2.20–2.31(m, 1H) 1.91–2.02(m, 1H) 1.78–1.89(m, 1H)1.66–1.77(m,8H) 1.28–1.40(m, 2H) 523  6 I-642

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-fluoro-phenyl)-pyridin-2-ylamine(400 MHz, DMSO-D6) d ppm 7.61(d, J=1.77 Hz,1H) 7.38(dd, J=8.97, 4.93 Hz,1H) 7.20–7.29(m, 3H) 6.99–7.07(m, 2H) 6.76(d, J=1.77 Hz,1H) 5.95(q,J=6.65 Hz, 1H) 5.70(s, 2H) 1.62(d, J=6.57 Hz, 3H) 395  1 I-643

6′-Amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-1H-[3,3′]-bipyridinyl-6-one0.0432 (500 MHz, DMSO-D6) d ppm 7.73(s, 1H) 7.73–7.46(m, 5H) 7.09(d,J=1.55 Hz, 1H) 6.42(d,J=9.5 Hz, 1H) 6.29(q, J=6.65 Hz, 1H) 1.84(d,J=6.60Hz, 3H) 394  3 I-644

5′-Bromo-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ylamine0.1958 (300 MHz, CDCl3-D1) d ppm 8.54(d, 2H) 7.80(m, 2H) 7.33(m, 1H)7.08(m, 1H) 6.93(s, 1H)6.12(q, J=6.7 Hz, 1H) 5.041(br. s, 2H) 1.88(d,J=6.7 Hz, 3H) 458[M + 2]  3 I-645

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-dimethylamino-phenyl)-pyridin-2-ylamine0.1572 (300 MHz, CDCl3-D1) d ppm 7.83(d, J=1.87 Hz,1H) 7.28(m, 4H)7.04(m, 1H) 6.98(d, J=1.76 Hz,1H) 6.75(m, 2H) 6.11(q, J=6.7 Hz, 1H)4.76(br. s, 2H) 2.97(s, 6H) 1.85(d, J=6.7Hz, 3H) 420  3 I-646

5-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-2′-methoxy-[3,3′]bipyridinyl-6-ylamine0.099 (300 MHz, CDCl3-D1) d ppm 8.10(s, 1H) 7.77(s, 1H) 7.50(m, 1H)7.30(m, 1H) 7.09(m, 2H)6.92(m, 1H) 6.06(d, J=6.7 Hz, 1H) 4.91(br. s,2H)3.87(s, 3H) 1.83(d, J=6.7 Hz, 3H) MS 408m/z  3 I-647

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-indol-5-yl)-pyridin-2-ylamine0.1664 (300 MHz, CDCl3-D1) d ppm 8.21(s, 1H) 7.93(m, 1H) 7.64(m, 1H)7.43(m, 1H) 7.32–7.21(m, 3H) 7.09–7.024(m, 2H) 6.58(m, 1H) 6.16(m, 1H)4.80(s, 2H) 3.50(s, 2H) 1.87(d,J=6.69 Hz, 3H) 416  3 I-648

(4-{6-Amino-5-[1-(2,6-dichloro-phenyl)-propoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone0.5533 (300 MHz, CDCl3-D1) d ppm 7.87(s, 1H) 7.42(m, 4H) 7.30(m, 3H)7.16(m, 1H) 7.05(s, 1H)5.92(m, 1H) 4.97(s, 2H) 4.61(br. s, 1H) 3.65(br.s, 2H) 2.85(br. s, 3H) 2.49(br. s, 1H) 2.41(m, 3H) 2.19(m, 1H) 1.08(m,6H) 513  1 I-649

[4-(6-Amino-5-benzyloxy-pyridin-3-yl)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone29% (400 MHz, DMSO-D6) d ppm 7.92(d, J=1.77 Hz,1H) 7.68(d, J=8.34 Hz,2H) 7.53(d, J=7.07 Hz,2H) 7.37–7.46(m, 5H) 7.33(m, 1H) 5.96(s,2H)5.25(s, 2H) 3.49(s, 2H) 3.09(s, 2H) 2.00(s, 2H) 1.84(s, 2H) 1.56(s, 1H)457  1 I-650

3-(2,6-Dichloro-3-fluoro-benzyloxy)-5-thiazol-2-yl-pyridin-2-ylamine0.3627 (300 MHz, CDCl3-D1) d ppm 8.25(d, J=1.79Hz, 1H) 7.76(d, J=3.30Hz) 7.36–7.26(m, 3H)7.20(m, 1H) 7.05(m, 1H) 6.17(q, J=6.7 Hz,1H)5.09(br. s, 2H) 1.86(d, J=6.7 Hz, 3H) 384 37 I-651

(4-{6-Amino-5-[1-(2-fluoro-6-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone1.5258 (400 MHz, DMSO-D6) d ppm 7.93(d, J=1.52 Hz,1H) 7.74–7.82(m, 3H)7.71 m, 3H) 7.62–7.67(m, 3H) 7.47(m, 4H) 7.38(m, 1H) 5.43(s, 2H)3.67(br.s, 2H) 3.51(br. s, 3H) 3.40(br. s, 1H)3.09(br. s, 2H) 2.00(br. s, 3H)1.83(br. s, 2H)1.53(br. s, 2H) 533  6 I-652

3-(2,6-Dichloro-3-fluoro-benzyloxy)-5-(1-methyl-1H-imidazol-2-yl)-pyridin-2-ylamine11% (300 MHz, CDCl3-D1) d ppm 7.90(d, J=1.67Hz, 1H) 7.30(m, 2H) 7.05(m,3H) 6.91(d,J=0.98 Hz, 1H) 6.10(q, J=6.7 Hz, 1H) 4.99(br.s, 2H) 3.57(s,3H) 1.83(d, J=6.7 Hz, 3H) 381 38 I-653

{4-[6-Amino-5-(2,4,6-trimethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone2% (400 MHz, DMSO-D6) d ppm 7.92(s, 1H) 7.90(s, 1H) 7.84(d, J=8.34 Hz,2H) 7.50(d, J=8.34Hz, 2H) 6.92(s, 2H) 5.27(s, 2H) 3.51(br. s,8H)3.09(br. s, 3H) 2.32(s, 6H) 2.25(s, 3H)1.99(br. s, 2H) 1.84(br. s, 2H)1.55(br. s, 2H) 499  6 I-654

{4-[6-Amino-5-(2,3,5,6-tetramethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone9% (400 MHz, DMSO-D6) d ppm 9.75(s, 1H) 7.88(s, 2H) 7.79(d, J=8.34 Hz,2H) 7.45(d, J=8.08Hz, 3H) 6.97(s, 1H) 5.28(s, 2H) 3.64(s, 1H)3.45(s, 2H)3.34(s, 1H) 3.04(s, 3H) 2.15(s,12H) 1.94(s, 3H) 1.79(s, 2H) 1.50(s, 2H)513  6 I-655

{4-[6-Amino-5-(2,4,6-trifluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone(400 MHz, DMSO-D6) d ppm 7.83(d, J=2.02 Hz,1H) 7.48(d, J=8.34 Hz, 3H)7.33(d, J=8.34 Hz,3H) 7.24(d, J=1.77 Hz, 1H) 7.12–7.22 (m, 2H)5.86(m,1H) 5.76(s, 2H) 4.19(br. s, 1H) 3.55(br. s, 1H) 2.96(br. s, 2H) 2.16(br.s, 1H) 1.83(br. s, 2H) 1.69(br. s, 5H) 1.60(d, J=5.67 Hz,5H) 1.30(br. s,2H) 525  6 I-656

(4-{6-Amino-5-[1-(2-fluoro-6-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone(400 MHz, DMSO-D6) d ppm 7.89(d, J=1.77 Hz,1H) 7.57–7.66(m, 3H)7.41–7.49(m, 2H)7.36(d, J=8.08 Hz, 2H) 7.19(d, J=1.77 Hz, 1H)5.85(s, 2H)5.80(s, 1H) 4.21(s, 1H) 3.57(br.s, 1H) 3.02(s, 2H) 2.22(s, 1H) 1.80(br.s, 2H)1.78(d, J=6.3 Hz, 3H) 1.66(s, 4H) 1.34(s, 2H) 557  6 I-657

6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-N-methyl-nicotinamidine(400 MHz, DMSO-D6) δ ppm 8.82(br. s, 1H)7.97(d, J=1.77 Hz, 1H)7.52–7.57(m, 1H)7.46(t, J=8.72 Hz, 1H) 7.05(d, J=1.26 Hz, 1H)6.73(br. s,1H) 6.06(quart., J=6.57 Hz, 1H)2.91(s, 3H) 1.78(d, J=6.57 Hz, 3H) 357 39I-658

6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-N-(2-morpholin-4-yl-ethyl)-nicotinamidine(400 MHz, DMSO-D6) δ ppm 9.07(br. s, 1H)7.94(d, J=1.52 Hz, 1H) 7.53(m,1H) 7.47 (m,1H) 6.97(s, 1H) 6.77(br. s, 1H) 6.06(s, 1H)3.55(quart,J=4.29 Hz, 2H) 3.54(m, 2H) 3.47(m, 2H) 2.54(t, J=6.06 Hz, 2H) 2.42(s,3H)1.78(d, J=6.82 Hz, 3H) 456 39 I-659

(4-{6-Amino-5-[1-(2,4,5-trifluoro-phenyl)-propoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone(400 MHz, DMSO-D6) d ppm 9.84(s, 1H) 7.91(d, J=1.52 Hz, 1H) 7.78–7.88(m,1H) 7.65–7.75(m, 3H) 7.57(dd, J=10.23, 3.66 Hz, 1H)7.46(d, J=8.34 Hz,2H) 5.91–5.98(m, 1H) 3.50(s, 2H) 3.40(s, 1H) 3.09(s, 2H)2.09(dt,J=14.08, 6.98 Hz, 2H) 1.99(s, 2H) 1.92(dt,J=13.90, 6.95 Hz, 2H)1.83(s, 2H) 1.55(s, 2H)0.92(t, J=7.33 Hz, 3H) 540  6 I-660

(4-{6-Amino-5-[1-(6-chloro-2-fluoro-3-methyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanoneNMR (400 MHz, DMSO-D6) d ppm 9.84(s, 1H)7.95(s, 2H) 7.65(d, J=8.34 Hz,2H) 7.53–7.60(m,2H) 7.48(s, 1H) 7.32–7.42(m, 2H) 6.25(q, J=6.48Hz, 1H)3.58(s, 2H) 3.49(s, 1H) 3.18(d, J=5.05Hz, 3H) 2.27(d, J=1.52 Hz, 5H)2.01–2.13(m,4H) 1.89(d, J=6.57 Hz, 5H) 1.64(s, 2H) 539  6 I-661

3-(1-{2-Amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-benzoicacid (400 MHz, DMSO-D6) d ppm10.14(s, 1H) 8.12(s, 1H) 7.93(s, 1H)7.76–7.87(m, 4H) 7.72(s,1H) 7.65(d, J=8.34 Hz, 2H) 7.53(ddd,J=15.92,7.83, 7.58 Hz, 2H) 7.40–7.47(m, 3H) 6.03–6.10(m, 1H) 4.55(s, 1H)3.64(s, 1H) 3.47(s,2H) 3.38(s, 1H) 3.07(s, 3H) 2.13(s, 1H) 1.98(s, 3H)1.78–1.89(m, 3H) 1.65(t, J=5.68 Hz,3H) 1.56(s, 2H) 1.31(d, J=6.57 Hz,2H) 516 6

TABLE 4 Met IC₅₀ MS m/z No. Structure Name (μM) Procedure ¹H-NMR (M + 1)II-1 

4-[5-Amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-phenol 1.35seeexamples (400 MHz, DMSO-d₆) δ 5.61(s, 2H), 6.09(s, 2H),6.79(d, 2H),7.45(t, 1H), 2.56(d, 2H), 7.76(d,2H), 7.99(s, 1H), 9.46(s, 1H) 362 II-2 

3-(2,6-Dichloro-benzyloxy)-5-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-pyrazin-2-ylamine0.825 seeexamples (400 MHz, DMSO-d₆) δ 2.41(m, 2H), 3.51(m,2H), 3.76(m,2H), 5.62(s, 2H), 6.28(s, 2H), 7.22(m, 2H), 7.48(m, 1H), 7.56(m, 2H),7.94(m,2H), 8.14(s, 1H) 465 II-3 

3-(2,6-Dichloro-benzyloxy)-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine0.74 seeexamples (400 MHz, DMSO-d₆) δ 2.45(m, 4H), 2.71(t,2H), 3.56(t,4H), 4.15(t, 2H), 5.61(s, 2H), 6.32(s, 2H), 6.86(d, 1H), 7.29(t, 1H),7.46(m, 2H),7.52(m, 1), 7.55(s, 1H), 7.57(d, 1H), 8.16(s, 1H) 475 II-4 

3-(2,6-Dichloro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine1.25 seeexamples (400 MHz, DMSO-d₆) δ 2.45(m, 4H), 2.71(m,2H), 3.59(t,4H), 4.11(t, 2H), 5.64(s, 2H), 6.18(s, 2H), 6.97(d, 2H), 7.46(t, 1H),7.56(d, 2H),7.86(d, 2H), 8.06(s, 1H) 475 II-5 

5-(4-Amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyrazin-2-ylamine 0.94seeexamples (400 MHz, DMSO-d₆) δ 5.19(s, 2H), 5.59(s, 2H),5.96(s, 2H),6.60(d, 2H), 7.45(t, 1H), 7.56(d,2H), 7.62(d, 2H), 7.91(s, 1H) 361 II-6 

4-[5-Amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-benzoic acid 1.75seeexamples (400 MHz, DMSO-d₆) δ 5.64(s, 2H), 6.52(s, 2H),7.46(m, 1H),7.56(m, 2H), 7.96(d, 2H), 8.07(d,2H), 8.27(s, 1H) 390 II-7 

{4-[5-Amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-phenyl)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone0.24 seeexamples (400 MHz, DMSO-d₆) δ 1.79(m, 10H), 2.64(m,4H), 3.45(m,3H), 5.64(s, 2H), 6.42(s, 2H), 7.49(m, 3H), 7.58(m, 2H), 7.98(d, 2H),8.00(s, 1H) 526 II-8 

{4-[5-Amino-6-(2,6-dichloro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone0.56 seeexamples (400 MHz, DMSO-d₆) δ 1.37(m, 2H), 1.66(m,4H), 1.85(m,2H), 2.32(m, 2H), 2.52(m, 4H),3.04(m, 2H), 3.92(m, 1H), 5.62(s, 2H),6.42(s,2H), 7.40(d, 2H), 7.46(t, 1H), 7.58(m, 2H), 8.00(d, 2H), 8.21(s,1H) 526 II-9 

2-Morpholin-4-yl-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide1.26 seeexamples (300 MHz, CDCl₃) δ 2.50(t, 4H), 2.92(t, 2H),3.29(t,2H), 3.72(t, 2H), 4.81(s, 2H), 5.67(d,2H), 7.05(m, 1H), 7.20(m, 1H),7.28(d, 2H),7.90(d, 2H), 8.04(s, 1H) 540 II-10 

2-Piperidin-1-yl-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide1.2 seeexamples (300 MHz, CDCl₃) δ 1.60(m, 2H), 1.63(m, 4H),2.49(m, 4H),2.90(t, 2H), 3.26(t, 2H), 4.85(s,2H), 5.67(d, 2H), 7.05(m, 1H), 7.20(m,1H),7.29(d, 2H), 7.89(d, 2H), 8.04(s, 1H) 538 II-11 

2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide0.65 seeexamples (300 MHz, CDCl₃) δ 1.63(m, 2H), 1.90(m, 2H),2.27(t,2H), 2.80(m, 2H), 2.92(t, 2H), 4.86(s,2H), 5.67(d, 2H), 7.05(m, 1H),7.20(m, 1H),7.28(d, 2H), 7.90(d, 2H), 8.04(s, 1H) 554 II-12 

2-Pyrrolidin-1-yl-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide0.58 seeexamples (300 MHz, CDCl₃) δ 1.83(m, 4H), 2.56(m, 4H),3.04(t,2H), 3.28(t, 2H), 4.91(s, 2H), 5.67(d,2H), 7.05(m, 1H), 7.20(m, 1H),7.27(d, 2H),7.88(d, 2H), 8.03(s, 1H) 524 II-13 

2-[(3R)-3-Hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide1.59 seeexamples (300 MHz, CDCl₃) δ 1.85(m, 1H), 2.25(m, 2H),2.55(m,1H), 2.84(d, 1H), 3.02(m, 3H), 3.26(m,2H), 4.43(m, 1H), 4.82(s, 2H),5.67(d, 2H), 7.05(m, 1H), 7.20(m, 1H), 7.35(d, 2H), 7.88(d, 2H),8.04(s,1H) 540 II-14 

2-[(2S)-2-Hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide1.78 seeexamples (300 MHz, CDCl₃) δ 1.85(m, 4H), 2.20(m, 1H),2.70(m,2H), 3.05(m, 2H), 3.30–3.70(m, 3H),3.95(m, 1H), 4.79(s, 2H), 5.67(d,2H), 7.05(m,1H), 7.20(m, 1H), 7.32(d, 2H), 7.88(d, 2H), 8.05(s, 1H) 554II-15 

2-(Cyclopropylmethyl-amino)-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide1.28 seeexamples ¹H NMR (300 MHz, CDCl₃) δ 0.14(m, 2H), 0.52(m, 2H),0.95(m, 1H), 2.50(d, 2H), 3.21(m, 4H),4.86(s, 2H), 5.67(d, 2H), 7.05(m,1H), 7.20(m,1H), 7.30(d, 2H), 7.89(d, 2H), 8.04(s, 1H) 524 II-16 

2-Dimethylamino-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide0.91 seeexamples (300 MHz, CDCl₃) δ 2.30(s, 6H), 2.86(t, 2H),3.21(t,2H), 4.83(s, 2H), 5.67(d, 2H), 7.05(m,1H), 7.18(m, 1H), 7.28(d, 2H),7.88(d, 2H), 8.05(s, 1H) 498 II-17 

2-Diethylamino-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide0.46 seeexamples (300 MHz, CDCl₃) δ 1.08(t, 6H), 2.61(q, 4H),3.03(t,2H), 3.23(t, 2H), 4.80(s, 2H), 5.67(d,2H), 7.05(m, 1H), 7.19(m, 1H),7.27(d, 2H),7.88(d, 2H), 8.04(s, 1H) 526 II-18 

2-(4-Acetyl-piperazin-1-yl)-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide1.5 seeexamples (300 MHz, CDCl₃) δ 2.08(s, 3H), 2.46(m, 4H),2.93(t, 2H),3.30(t, 2H), 3.47(t, 2H), 3.62(t, 2H),4.82(s, 2H), 5.67(s, 2H), 7.05(m,1H), 7.20(m,1H), 7.28(d, 2H), 7.91(d, 2H), 8.05(s, 1H) 581 II-19 

2-[4-(2-Hydroxy-acetyl)-piperazin-1-yl]-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide0.45 seeexamples (300 MHz, CDCl₃) δ 2.48(t, 4H), 2.93(t, 2H),3.30(m,4H), 3.55(brs, 1H), 3.67(t, 2H), 4.14(s,2H), 4.84(s, 2H), 5.67(s, 2H),7.05(m, 1H), 7.20(m, 1H), 7.27(d, 2H), 7.92(d, 2H), 8.05(s, 1H) 597II-20 

2-Cyclopropylamino-ethanesulfonic acid{4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide1.29 seeexamples (300 MHz, CDCl₃) δ 0.37(m, 2H), 0.49(m, 2H),2.14(m,1H), 3.24(m, 4H), 4.93(s, 2H), 5.67(d,2H), 7.05(m, 1H), 7.20(m, 1H),7.28(d, 2H),7.90(d, 2H), 8.03(s, 1H) 510 II-21 

2-[(3R)-3-Hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide1.38 seeexamples (300 MHz, CDCl₃) δ 1.60–2.0(m, 5H), 2.15 (m,1H),2.55–2.70(m, 2H), 2.90–3.15(m, 2H), 3.3–3.62(m, 2H), 3.89(dd, J=3.0,11.3 Hz, 1H),4.92(s, 2H), 5.66(s, 2H), 6.95–7.60(m, 5H), 7.55–7.70(m,2H), 7.77(s, 1H), 8.10(s, 1H) 554 II-22 

2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide0.7 seeexamples (300 MHz, CDCl₃) δ 1.40–1.60(m, 2H), 1.75–1.88(m, 2H),2.21(t, J=9.0 Hz, 2H), 2.65–2.75 (m,2H), 2.85–2.95(m, 2H), 3.20–3.35(m,2H), 3.69(m, 1H), 5.17(s, 2H), 5.68(s, 2H), 6.92–7.02(m,1H),7.08–7.20(m, 1H), 7.30–7.45(m, 2H), 7.69(s, 1H), 7.76(d, J=7.5 Hz, 1H),8.14(s, 1H) 555 II-23 

2-(4-Acetyl-piperazin-1-yl)-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl]-amide2.79 seeexamples (300 MHz, CDCl₃) δ 2.03(s, 3H), 2.30–2.40(m,2H),2.75–2.85(m, 2H), 3.20–3.40(m, 4H), 3.45–3.55(m, 2H), 5.35(s, 2H),5.68(s, 2H), 6.95–7.02(m, 1H), 7.05–7.20(m, 1H), 7.30–7.45(m,2H),7.64(s, 1H), 7.76(d, J=7.3 Hz, 1H), 8.13(s,1H), 8.52(s, 1H) 582II-24 

2-Piperidin-1-yl-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide3.5 seeexamples (300 MHz, CDCl₃) δ 1.30–1.60(m, 6H), 2.30–2.45(m, 4H),2.75–2.90(m, 2H), 3.15–3.30(m, 2H),5.10(s, 2H), 5.66(s, 2H),6.95–7.05(m, 1H), 7.10–7.20(m, 1H), 7.25–7.40(m, 2H), 7.60–7.75(m,2H),8.10(s, 1H) 539 II-25 

2-Diethylamino-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide3.7 seeexamples (300 MHz, CDCl₃) δ 0.95–1.05(m, 6H), 2.45–2.55(m, 4H),2.95–3.10(m, 2H), 3.15–3.25(m, 2H),5.11(s, 2H), 5.67(s, 2H),6.90–7.15(m, 2H), 7.20–7.40(m, 2H), 7.55–7.70(m, 2H), 8.10(s, 1H) 527II-26 

2-Morpholin-4-yl-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide3.3 seeexamples (300 MHz, CDCl₃) δ 2.30–2.50(m, 2H), 2.80–3.00(m, 2H),3.20–3.40(m, 2H), 3.50–3.75(m, 4H),5.21(s, 2H), 5.67(s, 2H),6.95–7.08(m, 1H), 7.10–7.20(m, 1H), 7.30–7.50(m, 2H), 7.67(s,1H),7.74(d, J=7.5 Hz, 1H), 8.12(s, 1H) 541 II-27 

2-Pyrrolidin-1-yl-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide1.8 seeexamples (300 MHz, CDCl₃) δ 1.62–1.82(m, 4H), 2.40–2.55(m, 4H),2.92–3.00(m, 2H), 3.25–3.35 (m, 2H),5.24(s, 2H), 5.67(s, 2H),6.95–7.08(m, 1H),7.10–7.20(m, 1H), 7.25–7.40(m, 2H), 7.63(s,1H), 7.73(d,J=7.1 Hz, 1H), 8.12(s, 1H) 525 II-28 

2-Dimethylamino-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide2.28 seeexamples (300 MHz, CDCl₃) δ 2.27(s, 6H), 2.86(t, J=6.4Hz, 2H),3.23(t, J=6.4 Hz, 2H), 5.08(s, 2H),5.67(s, 2H), 7.00–7.45(m, 4H),7.65–7.75(m,2H), 8.11(s, 1H) 499 II-29 

2-[4-(2-Hydroxy-acetyl)-piperizin-1-yl]-1-yl]-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide1.82 seeexamples (300 MHz, CDCl₃) δ 2.43(t, 4H), 2.92(t, 2H),3.20(t,2H), 3.33(t, 2H), 3.54(br s, 1H), 3.61(t,2H), 4.08(s, 2H), 5.18(br s,2H), 5.67(s, 2H),7.00–7.45(m, 4H), 7.65–7.75(m, 2H), 8.11(s, 1H) 597II-30 

2-(Cyclopropylmethyl-amino)-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide1.84 seeexamples (300 MHz, CDCl₃) δ 0.07(m, 2H), 0.44(m, 2H),0.89(m,1H), 2.45(d, 2H), 3.16(t, 2H), 3.29 (t,2H), 5.27(br s, 2H), 5.67(s, 2H),7.07(m, 1H),7.20(m, 1H), 7.41(m, 2H), 7.65(s, 1H), 7.77(m,1H), 8.12(s,1H) 524 II-31 

2-[(3R)-3-Hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide2.16 seeexamples (300 MHz, CDCl₃) δ 1.80(m, 1H), 2.20(m, 2H),2.50(m,1H), 2.70–3.20(m, 5H), 3.32(m, 2H),4.35(m, 1H), 5.12(s, 2H), 5.68(s,2H), 7.05(m,1H), 7.20(m, 1H), 7.40(m, 2H), 7.73(m, 2H),8.15(s, 1H) 540II-32 

2-Cyclopropylamino-ethanesulfonic acid{3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-amide2.13 seeexamples (300 MHz, CDCl₃) δ 0.25–0.50(m, 4H), 2.09(m,1H),3.15–3.40(m, 4H), 5.37(s, 2H), 5.68(s, 2H),7.07(m, 1H), 7.18(m, 1H),7.42(m, 2H), 7.62(m, 1H), 7.77(m, 1H), 8.13(s, 1H) 510 II-33 

4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzoicacid seeexamples 392 II-34 

{4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone0.15 seeexamples (300 MHz, CDCl₃) δ 1.5–2.2(m, 10H), 2.65(m,4H), 3.50(m,2H), 4.42(m, 1H), 4.86(br s, 2H),5.68(d, J=1.3 Hz, 2H), 7.05(m, 1H),7.19(m,1H), 7.57(m, 2H), 7.96(d, 2H), 8.12(s, 1H) 528 II-35 

4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide0.13 seeexamples (300 MHz, CDCl₃) δ 1.87(m, 4H), 2.73(m, 4H),2.85(t,2H), 3.64(m, 2H), 4.91(s, 2H), 5.68(d,2H), 7.05(m, 1H), 7.20(m, 1H),7.89(d, 2H),7.99(d, 2H), 8.13(s, 1H) 489 II-36 

{4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone0.37 seeexamples (300 MHz, CDCl₃) δ 1.80–2.40(m, 2H), 2.24(s,3H),3.30–3.90(m, 5H), 5.71(s, 2H), 7.25(m,1H), 7.35(m, 1H), 7.60(m, 2H),8.03(d, 2H),8.10(s, 1H) 461 II-37 

N-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-4-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzamide1.35 seeexamples (300 MHz, CDCl₃) δ 2.10(s, 3H), 2.52(m, 4H),2.66(t,2H), 3.40–3.80(m, 6H), 4.94(s, 2H), 5.68(s, 2H), 6.75(brs, 1H), 7.05(m,1H), 7.20(m,1H), 7.84(d, 2H), 8.00(d, 2H), 8.14(s, 1H) 545 II-38 

4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(3-pyrrolidin-1-yl-propyl)-benzamide0.58 seeexamples (300 MHz, CDCl₃) δ 1.91(m, 6H), 2.72(m, 4H),2.82(t,2H), 3.61(m, 2H), 4.93(s, 2H), 5.69(d,2H), 7.05(m, 1H), 7.20(m, 1H),7.89(d, 2H),7.97(d, 2H), 8.12(s, 1H), 8.73(s, 1H) 503 II-39 

{4-[5-Amino-8-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone0.67 seeexamples (300 MHz, CDCl₃) δ 1.70–2.10(m, 1H), 2.24(s,3H),2.34(s, 3H), 2.60–2.90(m, 1H), 3.30–4.00(m, 4H), 4.90(s, 2H), 5.68(d,2H), 7.10(m, 1H),7.20(m, 1H), 7.60(m, 2H), 7.97(d, 2H), 8.13(s, 1H) 489II-40 

{4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-methanone0.46 seeexamples (300 MHz, CD₃OD) δ 1.80–2.40(m, 2H), 2.24(s,3H),3.30–3.90(m, 5H), 5.71(s, 2H), 7.25(m,1H), 7.35(m, 1H), 7.60(m, 2H),8.03(d, 2H),8.10(s, 1H) 461 II-41 

{4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone0.48 seeexamples (300 MHz, CDCl₃) δ 0.9–1.2(m, 6H), 2.2–3.2(m,6H),4.91(s, 2H), 5.68(s, 2H), 7.10(m, 1H), 7.20(m, 1H), 7.48(d, 2H), 7.97(d,2H), 8.12(s, 1H) 489 II-42 

{4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone0.33 seeexamples (300 MHz, CDCl₃) δ 1.60–3.40(m, 17H), 4.89(s,2H),5.68(d, 2H), 7.10(m, 1H), 7.20(m, 1H),7.47(d, 2H), 7.96(d, 2H), 8.11(s,1H) 528 II-43 

4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(3-morpholin-4-yl-propyl)-benzamide0.59 seeexamples (300 MHz, CDCl₃) δ 1.83(m, 2H), 2.60(m, 6H),3.61(m,2H), 3.76(m, 4H), 4.93(s, 2H), 5.70(d,2H), 7.05(m, 1H), 7.20(m, 1H),7.88(d, 2H),8.00(d, 2H), 8.14(s, 1H) 518 II-44 

4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(1-methyl-piperidin-4-yl)-benzamide0.5 seeexamples (300 MHz, CDCl₃) δ 1.80(m, 2H), 2.07(m, 2H),2.22(m, 2H),2.34(s, 3H), 2.88(m, 2H), 4.04(m,2H), 4.92(s, 2H), 5.69(d, 2H), 6.03(d,1H), 7.05(m, 1H), 7.20(m, 1H), 7.82(d, 2H), 7.98(d, 2H),8.13(s, 1H) 489II-45 

4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide1.11 seeexamples (300 MHz, CD₃OD) δ 2.68(m, 6H), 3.60(m, 2H),3.75(m,4H), 5.72(s, 2H), 7.25(m, 1H), 7.35(m,1H), 7.88(d, 2H), 8.05(d, 2H),8.12(s, 1H) 504 II-46 

{4-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone0.68 seeexamples (300 MHz, CDCl₃) δ 2.39(s, 3H), 2.48(m, 4H),3.69(m,4H), 4.89(s, 2H), 5.69(s, 2H), 7.08(m,1H), 7.20(m, 1H), 7.52(d, 2H),7.95(d, 2H), 8.08(s, 1H) 474 II-47 

3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzoicacid seeexamples 392 II-48 

{3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone2.85 seeexamples (300 MHz, CDCl₃) δ 2.33(s, 3H), 2.46(m, 4H),3.68(m,4H), 4.86(br s, 2H), 5.67(s, 2H), 7.08(m, 1H), 7.20(m, 1H), 7.35(d, 1H),7.47(t, 1H),7.95(m, 2H), 8.10(s, 1H) 474 II-49 

{3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3R)-3-amino-pyrrolidin-1-yl]-methanone1.02 seeexamples (300 MHz, CD₃OD) δ 2.12(m, 1H), 2.44(m,1H),3.52–4.05(m, 5H), 5.77(s, 2H), 7.24(m, 1H),7.38(m, 1H), 7.54(m, 2H),8.02(s, 1H),8.12(m, 2H) 460 II-50 

{3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3S)-3-amino-pyrrolidin-1-yl]-methanone0.91 seeexamples (300 MHz, CD₃OD) δ 2.12(m, 1H), 2.44(m,1H),3.52–4.05(m, 5H), 5.77(s, 2H), 7.24(m, 1H), 7.38(m, 1H), 7.54(m,2H), 8.02(s, 1H), 8.12(m, 2H) 460 II-51 

{3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone2.56 seeexamples (300 MHz, CDCl₃) δ 0.99(br d, 3H), 1.15(br d,3H),2.42(m, 1H), 2.70(m, 1H), 2.84(m, 1H),2.93(m, 1H), 3.66(m, 1H), 4.67(m,1H), 4.92(brs, 2H), 5.66(s, 2H), 7.05(m, 1H), 7.20(m, 1H),7.35(m, 1H),7.47(t, 1H), 7.97(m, 2H),8.10(s, 1H) 488 II-52 

3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(3-morpholin-4-yl-propyl)-benzamide4.2 seeexamples (300 MHz, CDCl₃) δ 1.82(m, 2H), 2.50(m, 4H),2.56(m, 2H),3.67(m, 6H), 4.88(br s, 2H), 5.68(s, 2H), 7.05(m, 1H), 7.19(m, 1H),7.48(t, 1H),7.70(d, 1H), 7.90(m, 1H), 8.06(d, 1H), 8.14(s,1H), 8.38(t,J=1.6 Hz, 1H) 519 II-53 

{3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone0.83 seeexamples (300 MHz, CDCl₃) δ 1.60(m, 2H), 1.80(m, 4H),1.88(m,2H), 2.00(m, 2H), 2.32(m, 1H), 2.61(m, 4H), 2.56(m, 2H), 3.00(m, 2H),3.82(m, 1H),4.66(m, 1H), 4.93(br s, 2H), 5.66(s, 2H), 7.06(m, 1H),7.18(m, 1H), 7.32(dt, 1H), 7.46(t, 1H),7.70(d, 1H), 7.97(m, 2H), 8.09(d,J=3.6Hz, 1H) 528 II-54 

{3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(3S)-3-dimethylamino-pyrrolidin-1-yl]-methanone1.45 seeexamples (300 MHz, CDCl₃) δ 1.85(m, 1H), 2.10(m, 1H),2.21(s,3H), 2.31(s, 3H), 2.75(m, 1H), 3.42(m,1H), 3.64(m, 2H), 3.92(m, 1H),4.93(br s, 2H),5.67(s, 2H), 7.06(m, 1H), 7.18(m, 1H), 7.46(m,2H),7.97(m, 1H), 8.09(m, 2H) 488 II-55 

3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(2-pyrrolidin-1-yl-ethyl)-benzamide1.6 seeexamples (300 MHz, CDCl₃) δ 1.82(m, 4H), 2.69(m, 4H),2.84(m, 2H),3.65(m, 2H), 4.93 (br s, 2H), 5.68(s, 2H), 7.06(m, 1H), 7.18(m, 1H),7.22(m, 1H),7.49(t, J=7.7 Hz, 1H), 7.77(d, J=7.8 Hz, 1H),8.04(dt, J=7.9Hz, 1.5 Hz, 1H), 8.13(s, 1H),8.38(t, J=1.5 Hz, 1H) 488 II-56 

3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(1-methyl-piperidin-4-yl)-benzamide0.9 seeexamples (300 MHz, CDCl₃) δ 1.71(m, 2H), 2.11(m, 2H),2.28(t, 2H),2.95(m, 2H), 4.11(m, 1H), 4.89(s,2H), 5.69(s, 2H), 6.28(m, 1H), 7.08(m,1H), 7.18(m, 1H), 7.45(t, 1H), 7.68(d, 1H), 8.06(d, 1H),8.11(s, 1H),8.35(s, 1H) 488 II-57 

{3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-phenyl}-[(2S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone0.63 seeexamples (300 MHz, CDCl₃) δ 2.02(m, 10H), 2.75(m, 4H),3.49(m,2H), 4.51(m, 1H), 4.89(s, 2H), 5.69(s,2H), 7.08(m, 1H), 7.20(m, 1H),7.48(m, 2H),7.98(m, 1H), 8.07(m, 1H), 8.11(s, 1H) 528 II-58 

3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide2.5 seeexamples (300 MHz, CD₃OD) δ 2.51(m, 4H), 2.65(t, 2H),3.58(t, 2H),3.69(m, 4H), 5.72(s, 2H), 7.20(m,1H), 7.35(m, 1H), 7.52(t, 1H), 7.76(d,1H), 8.12(m, 2H), 8.41(s, 1H) 504 II-59 

N-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-3-[5-amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-benzamide2.77 seeexamples (300 MHz, CD₃OD) δ 2.08(s, 3H), 2.59(m, 6H),3.57(m,6H), 5.71(s, 2H), 7.21(m, 1H), 7.37(m,1H), 7.50(t, 1H), 7.75(d, 1H),8.08(m, 2H),8.39(s, 1H) 545 II-60 

3-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-N-(3-pyrrolidin-1-yl-pyropyl)-benzamide1.48 seeexamples (300 MHz, CDCl₃) δ 1.79(m, 4H), 1.88(t, 2H),2.65(m,4H), 2.78(t, 2H), 3.65 (m, 2H), 4.86(s,2H), 5.69(s, 2H), 7.06(m, 1H),7.21(m, 1H),7.45(t, 1H), 7.68(d, 1H), 8.06(d, 1H), 8.16(s,1H), 8.40(s,1H), 8.69(m, 1H) 502 II-61 

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(1H-indol-5-yl)-pyrazin-2-ylamineseeexamples 387 II-62 

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(3-pyrrolidin-1-ylmethyl-1H-indol-5-yl)-pyrazin-2-ylamine0.35 seeexamples (300 MHz, CDCl₃) δ 1.78(m, 4H), 2.66(m, 4H),3.89(s,2H), 4.89(s, 2H), 5.69(s, 2H), 7.08(m,1H), 7.18(m, 2H), 7.39(d, 1H),7.79(d, 1H), 8.08(s, 1H), 8.18(s, 1H), 8.79(s, 1H) 470 II-63 

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(3-diethylaminomethyl-1H-indol-5-yl)-pyrazin-2-ylamine0.73 seeexamples (300 MHz, CDCl₃) δ 1.11(m, 6H), 2.69(m, 4H),3.80(s,2H), 4.69(s, 2H), 5.77(s, 2H), 7.02(m,1H), 7.21(m, 2H), 7.45(d, 1H),7.89(d, 1H), 8.22(m, 3H) 472 II-64 

1-(4-{5-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-1H-indol-3-ylmethyl}-piperazin-1-yl)-ethanone1.5 seeexamples (300 MHz, CDCl₃) δ 2.08(s, 3H), 2.55(m, 4H),3.45(m, 2H),3.64(m, 2H), 3.81(s, 2H), 4.78 (s,2H), 5.71(s, 2H), 7.08(m, 1H), 7.18(m,2H), 7.31(d, 1H), 7.79(d, 1H), 8.04(s, 1H), 8.22(s, 1H),8.49(s, 1H) 527II-65 

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-1H-indol-5-yl]-pyrazin-2-ylamine2.4 seeexamples (300 MHz, CDCl₃) δ 1.11(d, 6H), 1.98(m, 2H),2.98(m, 2H),3.87(m, 4H), 4.75(s, 2H), 5.78(s,2H), 7.08(m, 1H), 7.27(m, 2H), 7.48(d,1H),7.89(d, 1H), 8.19(s, 1H), 8.28(s, 2H) 514 II-66 

N-(1-{5-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-1H-indol-3-ylmethyl}-(3S)-pyrrolidin-3-yl)-acetamide0.55 seeexamples (300 MHz, CDCl₃) δ 1.69(m, 1H), 1.88(s, 3H),2.39(m,2H), 2.75(m, 2H), 3.08(m, 1H), 3.95 (m,2H), 4.50(m, 1H), 4.79(s, 2H),5.78(s, 2H), 6.01(m, 1H), 7.05(m, 1H), 7.18(m, 2H), 7.42(d, 1H),7.79(d,1H), 8.12(s, 1H), 8.21(s, 1H),8.28(s, 1H) 527 II-67 

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(3-piperidin-1-ylmethyl-1H-indol-5-yl)-pyrazin-2-ylamine0.51 seeexamples (300 MHz, CDCl₃) δ 1.49(m, 2H), 1.71(m, 4H),2.66(m,4H), 3.89(s, 2H), 4.79(s, 2H), 5.69 (s,2H), 7.08(m, 1H), 7.18(m, 1H),7.31(s, 1H),7.42(d, 1H), 7.78(d, 1H), 8.08(s, 1H), 8.18(s,1H), 8.69(brs, 1H) 484 II-68 

3-(2-Chloro-3,6-difluoro-benzyloxy)-5-(3-morpholin-4-ylmethyl-1H-indol-5-yl)-pyrazin-2-ylamine1.15 seeexamples (300 MHz, CDCl₃) δ 2.72(m, 4H), 3.80(m, 6H),4.73(s,2H), 5.73(s, 2H), 7.06(m, 1H), 7.20(m,1H), 7.46(d, 1H), 7.80(dd, 1H),8.12(s, 1H),8.25(s, 1H) 486 II-69 

3-[1-(2-Chloro-3,6-difluoro-phenyl)-2-methyl-propoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine10.58 seeexamples (400 MHz, DMSO-d₆) δ 0.89(d, 3H), 1.19 (d,3H), 2.47(m,4H), 2.56(m, 1H), 2.68(t, 2H), 3.56(t, 4H), 4.07(t, 2H), 5.96(d, 1H),6.28(s, 2H),6.89(d, 2H), 7.26(m, 1H), 7.38(m, 1H), 7.63(d,2H), 7.95(s,1H) 519 II-70 

3-[1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine;compoundwith trifluoro-acetic acid 0.51 seeexamples (400 MHz, DMSO-d₆) δ 1.78(d,3H), 3.21(m,2H), 3.51(m, 2H), 3.54(m, 2H), 3.74(m, 2H),3.98(m, 2H),4.38(t, 2H), 6.34(br s, 2H), 6.42(m, 1H), 6.97(d, 2H), 7.25(m, 1H),7.38(m, 1H),7.66(d, 2H), 7.86(s, 1H) 491 II-71 

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrazin-2-ylamine;compoundwith trifluoro-acetic acid 0.3 seeexamples (400 MHz, DMSO-d₆) δ 1.79(d,3H), 3.21(m,2H), 3.46(m, 2H), 3.57(m, 2H), 3.74(m, 2H),3.95(m, 2H),4.36(t, 2H), 6.34(br s, 2H), 6.49(m, 1H), 6.94(d, 2H), 7.37(t, 1H),7.48(m, 1H),7.66(d, 2H), 7.98(s, 1H) 491 II-72 

N-(4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-methanesulfonamideseeexamples (400 MHz, DMSO-d₆) δ 1.78(d, 3H), 2.96(s, 3H),6.41(m, 3H),7.15(d, 2H), 7.26(m, 1H), 7.37(m,1H), 7.64(d, 2H), 8.00(s, 1H), 9.72(s,1H) 455 II-73 

2-Pyrrolidin-1-yl-ethanesulfonicacid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amideseeexamples (300 MHz, CDCl₃) δ 1.84(m, 7H), 2.56(m, 4H),3.04(m, 2H),3.25(m, 2H), 4.94(br s, 2H), 6.71(q, 1H), 6.95(m, 2H), 7.21(d, 2H),7.72(d, 2H),7.96(s, 1H) 538 II-74 

2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amideseeexamples (300 MHz, CDCl₃) δ 1.60(m, 2H), 1.82(m, 5H),2.23(m, 2H),2.77(m, 2H), 2.89(t, 2H), 3.26(t,2H), 3.74(m, 1H), 5.07(br s, 2H),6.70(q,1H), 7.00(m, 2H), 7.24(d, 2H), 7.73(d, 2H), 7.94(s, 1H) 568II-75 

2-Piperidin-1-yl-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amideseeexamples (300 MHz, CDCl₃) δ 1.49(m, 2H), 1.61(m, 4H),1.83(d, 3H),2.50(m, 4H), 2.86(m, 2H), 3.20(m,2H), 4.95(br s, 2H), 6.70(q, 1H),7.00(m, 2H),7.24(d, 2H), 7.74(d, 2H), 7.96(s, 1H) 552 II-76 

2-(Cyclopropylmethyl-amino)-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amideseeexamples (300 MHz, CDCl₃) δ 0.14(m, 2H), 0.50(m, 2H),0.95(m, 1H),1.82(d, 3H), 2.49(m, 2H), 3.20(m,4H), 4.73(br s, 1H), 5.02(br s, 2H),6.71(q, 1H),7.00(m, 2H), 7.25(d, 2H), 7.74(d, 2H),7.96(s, 1H) 538 II-77 

2-[(3R)-3-Hydroxy-pyrrolidin-1-yl]-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amidesee examples (300 MHz, CDCl₃) δ 1.79(m, 1H), 1.82(d, 3H),2.26(m, 2H),2.54(m, 1H), 2.82(m, 1H), 2.98(m, 2H), 3.08(m, 1H), 3.26(m, 2H),4.44(m,1H), 4.94(br s, 1H), 6.70(q, 1H), 7.00(m, 2H),7.29(d, 2H),7.73(d, 2H), 7.96(s, 1H) 554 II-78 

2-[(2S)-2-Hydroxymethyl-pyrrolidin-1-yl]-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amideseeexamples (300 MHz, CDCl₃) δ 1.79(m, 4H), 1.82(d, 3H),2.15(m, 1H),2.66(m, 2H), 2.98(m, 2H), 3.35(m, 1H), 3.48(m, 1H), 3.54(m, 1H),3.92(m,1H), 4.97(br s, 1H), 6.70(q, 1H), 7.00(m, 2H),7.28(d, 2H),7.71(d, 2H), 7.95(s, 1H) 568 II-79 

2-Dimethylamino-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amideseeexamples (300 MHz, CDCl₃) δ 1.82(d, 3H), 2.29(s, 6H),2.85(t, 2H),3.21(t, 2H), 5.00(br s, 2H), 6.71(q,1H), 7.00(m, 2H), 7.23(d, 2H),7.74(d, 2H), 7.96(s, 1H) 512 II-80 

2-Morpholin-4-yl-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amideseeexamples (300 MHz, CDCl₃) δ 1.82(d, 3H), 2.48(m, 4H),2.90(m, 2H),3.27(m, 2H), 3.71(m, 4H), 4.92(brs, 2H), 6.71(q, 1H), 7.00(m, 2H),7.24(d, 2H),7.74(d, 2H), 7.97(s, 1H) 554 II-81 

2-Diethylamino-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amideseeexamples (300 MHz, CDCl₃) δ 1.07(t, 6H), 1.82(d, 3H),2.60(q, 4H),3.02(t, 2H), 3.22(t, 2H), 4.95(br s,2H), 6.71(q, 1H), 7.00(m, 2H),7.22(d, 2H), 7.74(d, 2H), 7.96(s, 1H) 540 II-82 

2-Cyclopropylamino-ethanesulfonic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl]-phenyl)-amideseeexamples (300 MHz, CDCl₃) δ 0.38(m, 2H), 0.50(m, 2H),1.82(d, 3H),2.15(m, 1H), 3.24(m, 4H), 4.93(brs, 2H), 6.71(q, 1H), 7.00(m, 2H),7.21(d, 2H),7.74(d, 2H), 7.97(s, 1H) 540 II-83 

3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid 1.36 seeexamples 423 II-84 

(3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-[(3S)-3-amino-pyrrolidin-1-yl)-m-ethanone0.069 seeexamples (300 MHz, MeOD) δ 7.84(d, 1H), 7.71(m, 2H),7.38(m,3H), 7.10(m, 1H), 6.60(m, 1H), 4.86(s,2H), 4.20(m, 1H), 3.45–3.89(m,4H), 1.82(d,3H), 1.34(m, 1H), 0.89(m, 1H) 492 II-85 

(3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-[(3R)-3-amino-pyrrolidin-1-yl)-m-ethanone0.11 seeexamples (300 MHz, MeOD) δ 7.84(d, 1H), 7.71(m, 2H),7.38(m, 3H),7.10(m, 1H), 6.60(m, 1H), 4.86(s,2H), 4.20(t, 1H), 3.45–3.89(m, 4H),1.82(d, 3H),1.34(m, 1H), 0.89(m, 1H) 492 II-86 

(3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone0.15 seeexamples (300 MHz, CDCl₃) δ 8.04(d, 1H), 7.84(d, 2H),7.30(d,2H), 7.15(tert, 1H), 6.99(t, 1H), 5.89(m,1H), 4.89(s, 2H), 4.44(s, 1H),3.89(m, 1H), 3.65(m, 1H), 3.30(m, 2H), 2.85(m, 3H), 1.82(d,3H),0.89–2.20(m, 9H) 558 II-87 

N-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-3-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzamide0.186 seeexamples (300 MHz, CDCl₃) δ 8.04(d, 1H), 7.99(s, 1H),7.78(d,1H), 7.60(d, 1H), 7.34(m, 2H), 7.15(t,1H), 6.72(tert, 1H), 4.89(s, 2H),4.56(m, 6H),3.21(d, 3H), 2.60(t, 1H), 2.55(dd, 1H), 2.09(s,3H), 1.80(d,4H) 575 II-88 

(3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-[(2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone0.17 seeexamples (300 MHz, MeOD) δ 8.04(d, 1H), 7.84(d, 2H),7.35(m, 3H),7.20(m, 1H), 6.60(m, 1H),4.89(s, 2H), 4.44(s, 1H), 3.59(m, 1H),3.30(m,1H), 3.25(s, 2H), 3.16(m, 3H), 1.82(d, 3H),0.89–2.32(m, 9H) 559II-89 

3-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid seeexamples 406 II-90 

3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide0.21 seeexamples (300 MHz, CDCl₃) δ 8.20(s, 1H), 8.08(s, 1H),7.89(d,1H), 7.75(d, 1H), 7.44(t, 1H), 7.01(m,2H), 6.78(m, 1H), 6.20(s, 1H),4.98(s, 2H), 4.09(m, 1H), 2.97(m, 2H), 2.39(s, 3H), 2.29(t, 2H),2.12(m,2H), 1.90(d, 3H), 1.79(m, 2H) 502 II-91 

3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide0.15 seeexamples (300 MHz, CD₃OD) δ 8.15(s, 1H), 7.98(s, 1H),7.80(d,1H), 7.61(d, 1H), 7.35(m, 2H), 7.09(t,1H), 6.69(m, 1H), 3.44(t, 2H),2.55(m, 6H), 1.88(d, 3H), 1.80(m, 6H) 532 II-92 

(3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone0.15 seeexamples (300 MHz, CD-₃OD) δ 7.96(s, 1H), 7.76 (d, 1H),7.65(m,1H), 7.41(m, 2H), 7.21(d, 1H), 7.12(t,1H), 6.61(m, 1H), 4.68(m, 2H),3.62(m, 1H),3.05(m, 2H), 2.69(m, 6H), 2.45(m, 2H), 2.12(m, 2H), 1.86(d,3H), 1.48(m, 2H) 558 II-93 

4-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzoicacid seeexamples 408 II-94 

4-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide0.22 seeexamples (300 MHz, CDCl₃) δ 8.14(s, 1H), 7.92(d, 2H),7.84(d,2H), 7.50(m, 1H), 7.42(m, 1H), 7.20(m,1H), 6.75(s, 1H), 5.70(s, 2H),4.97(s, 2H), 3.74(m, 4H), 3.58(m, 2H), 2.62(m, 2H), 2.52(s, 4H) 520II-95 

4-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-N-(1-methyl-piperidin-4-yl)-benzamide0.081 seeexamples (300 MHz, CDCl₃) δ 8.14(s, 1H), 7.92(d, 2H),7.84(d,2H), 7.50(m, 1H), 7.42(m, 1H), 7.20(m,1H), 6.04(d, 1H), 5.75(s, 2H),5.01(s, 2H), 4.0(m, 1H), 2.85(d, 2H), 2.30(s, 3H), 2.20(t, 2H),2.12(d,2H), 1.59(m, 2H) 504 II-96 

3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide0.15 4 as inExampleII-84 (300 MHZ, CD3OD) δ 8.18(s, 1H), 7.98(s,1H),7.80(d, 1H), 7.61(d, 1H), 7.35(m, 2H), 7.12(t,1H), 6.75(q, 1H),3.44(t, 2H), 2.55(m, 6H),1.88(d, 3H), 1.80(m, 6H). 532 II-97 

3-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide0.35 4 as inExampleII-90 (300 MHZ, CDCl3) δ 8.38(s, 1H), 8.18(s,2H),7.92(m, 2H), 7.48(t, 1H), 7.02(m, 2H), 6.78(q,1H), 4.96(s, 2H),3.72(m, 2H), 3.18(m, 2H),2.83(m, 2H), 2.22(m, 2H), 2.08(m, 4H), 1.83(d,3H), 1.70(m, 2H). 516 II-98 

3-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide0.21 4 as inExampleII-90 (300 MHZ, CDCl3) δ 8.20(s, 1H), 8.08(s,1H),7.89(d, 1H), 7.75(d, 1H), 7.44(t, 1H), 7.01(m,2H), 6.78(q, 1H), 6.20(bd, 1H), 4.98(s, 2H),4.09(m, 1H), 2.97(m, 2H), 2.39(s, 3H), 2.29(m,2H), 2.12(m, 2H), 1.90(d, 3H), 1.79(m, 2H). 502 II-99 

3-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide0.18 4 as inExampleII-90 (300 MHZ, CDCl3) δ 8.19(s, 1H), 8.09(s,1H),7.88(d, 1H), 7.78(d, 1H), 7.48 (t, 1H), 7.06(bm, 1H), 6.96(m, 2H),6.75(q, 1H), 5.08(s,2H), 3.68(m, 2H), 2.88(m, 2H), 2.68(m, 4H),1.86(m,7H). 502 II-100

3-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide0.31 4 as inExampleII-90 (300 MHZ, CDCl3) δ 8.17(s, 1H), 8.08(s,1H),7.88(d, 1H), 7.68(d, 1H), 7.48 (t, 1H), 6.98(m,2H), 6.80 (bt, 1H),6.74(q, 1H), 5.02(s, 2H),3.76(m, 4H), 3.68(m, 2H), 2.68(m, 2H), 2.58(m,4H), 1.85(d, 3H). 518 II-101

N-[2-(4-Acetyl-piperazin-1-yl)ethyl]-3-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzamide0.64 4 as inExampleII-90 (300 MHZ, CDCl3) δ 8.16(s, 1H), 8.03(s,1H),7.86(d, 1H), 7.68(d, 1H), 7.40(t, 1H), 6.98(m,3H), 6.71(q, 1H),5.13(s, 2H), 3.69(m, 4H),3.51(m, 2H), 2.80(m, 2H), 2.66(m, 4H), 2.08(s,3H), 1.83(d, 3H). 559 II-102

(3-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone4 as inExampleII-90 (300 MHZ, CDCl3) δ 8.02(s, 1H), 7.82 (m, 2H),7.41(t,1H), 7.28(m, 1H), 6.95(m, 2H), 6.71(q,1H), 5.00(s, 2H), 3.85(m, 2H),3.46(m, 2H),2.36(m, 4H), 2.33(s, 3H), 1.83(d, 3H). 488 II-103

(3-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone4 as inExampleII-90 (300 MHZ, CDCl3) δ 8.02(s, 1H), 7.80(m, 2H),7.41(t,1H), 7.29(m, 1H), 6.95(m, 2H), 6.69(q,1H), 4.97(s, 2H), 4.72(m, 1H),3.83(m, 1H),2.81(m, 7H), 1.83(d, 3H), 2.10–1.70(m, 8H). 542 II-104

(3-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone4 as inExampleII-90 (300 MHZ, CDCl3) δ 8.03(s, 1H), 7.80(m, 2H),7.41(t,1H), 7.29(m, 1H), 6.95(m, 2H), 6.70(q,1H), 5.00(s, 2H), 4.68 (m, 1H),3.56(m, 1H),2.75(m, 3H), 2.42(m, 1H), 1.83(d, 3H),1.57(m, 1H), 1.15(m,3H), 0.96(m, 3H). 502 II-105

(3-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone4 as inExampleII-90 (300 MHZ, CDCl3) δ 8.04(s, 1H), 7.83 (m, 2H),7.39(m,2H), 6.98(m, 2H), 6.70(q, 1H), 5.00(s, 2H), 4.47(m, 1H), 3.50(m, 2H),3.00(m,5H), 2.30(m, 3H), 2.00(m, 5H), 1.83(d, 3H),1.53(m, 1H). 542II-106

(3-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone4 as inExampleII-90 (300 MHZ, CDCl3) δ 8.02(s, 1H), 7.83 (m, 2H),7.40(m,2H), 6.98(m, 2H), 6.70(q, 1H), 4.98(s, 2H), 3.75(m, 4H), 3.61–3.15(m,1H), 2.15(m, 1H), 1.85(d, 3H), 1.95–1.75(m, 3H). 300 II-107

(3-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone4 as inExampleII-90 (300 MHZ, CDCl3) δ 8.02(s, 1H), 7.83(m, 2H),7.40(m,2H), 6.98(m, 2H), 6.70(q, 1H), 4.98(s, 2H), 3.75(m, 4H), 3.61–3.15(m,1H), 2.15(m, 1H), 1.85(d, 3H), 1.95–1.75(m, 3H). 300 II-108

4-{-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid 3 as inExampleI-211 406 II-109

4-{-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide0.1 4 as inExampleII-109 (300 MHZ, CDCl3) δ 8.28 (bm, 1H), 8.04(m,3H),7.84(d, 2H), 6.95(m, 2H), 6.71(q, 1H),5.03(s, 2H), 3.85(m, 2H), 3.72(m,2H), 3.18(m, 2H), 2.82(m, 2H), 2.25(m, 4H), 2.08(m,2H), 1.87(d, 3H). 516II-110

(4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone0.16 4 as inExampleII-109 (300 MHZ, CDCl3) δ 7.99(s, 1H), 7.78(d,2H),7.43(d, 2H), 7.29(m, 1H), 6.85(t, 1H), 6.94(q,1H), 5.07(s, 2H),3.75(m, 2H), 3.50(m, 2H),2.43(m, 4H), 2.33(s, 3H), 1.84(d, 3H). 488II-111

(4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone0.17 4 as inExampleII-109 (300 MHZ, CDCl3) δ 8.02(s, 1H), 7.81(d,2H),7.40(d, 2H), 6.99(m, 2H), 6.71(q, 1H), 5.02(s,2H), 4.64(m, 1H),3.85(m, 1H), 2.99(m, 2H),2.67(m, 4H), 2.38(m, 1H), 1.90(m, 9H),1.62(m,2H). 542 II-112

4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone0.19 4 as inExampleII-109 (300 MHZ, CDCl3) δ 8.02(s, 1H), 7.81(d,2H),7.38(d, 2H), 6.99(m, 2H), 6.71(q, 1H), 4.99(s,2H), 4.65(m, 1H),3.65(m, 1H), 2.88(m, 2H),2.68(m, 1H), 2.41(m, 1H), 1.84(d, 3H), 1.64(m,1H), 1.18(s, 3H), 1.06(s, 3H). 502 II-113

(4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone0.18 4 as inExampleII-109 (300 MHZ, CDCl3) δ 8.07(s, 1H), 7.81(d,2H),7.53(d, 2H), 6.95(m, 2H), 6.69(q, 1H), 4.99(s,2H), 4.45(m, 1H),3.55(m, 2H), 2.95(m, 4H),1.90–2.3(m, 9H), 1.82(d, 3H), 1.65(m, 1H). 542II-114

(4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone0.13 4 as inExampleII-109 (300 MHZ, CDCl₃) δ 8.02(s, 1H), 7.81(d,2H),7.53(d, 2H), 6.95(m, 2H), 6.69(q, 1H), 4.99(s,2H), 4.45(m, 1H),3.55(m, 2H), 2.95(m, 4H),2.21(m, 3H), 1.92(m, 6H), 1.82(d, 3H),1.59(m,1H). 542 II-115

(4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone0.078 4 as inExampleII-109 (300 MHZ, CD3OD) δ 8.02(s, 1H), 7.81(d,2H),7.53(d, 2H), 7.01(m, 2H), 6.69(q, 1H), 4.91(s,2H), 3.85(m, 1H),3.71(m, 2H), 3.55(m, 1H),2.18(m, 1H), 1.85(d, 3H), 1.75(m, 1H),1.42(m,3H). 574 II-116

4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide0.19 4 as inExampleII-109 (300 MHZ, CDCl3) δ 8.06(s, 1H), 7.82(m,4H),7.00(m, 2H), 6.72(m, 2H), 5.04(s, 2H), 4.09(m, 1H), 2.97(m, 2H),2.39(s, 3H), 2.29(m,2H), 2.12(m, 2H), 1.90(d, 3H), 1.79(m, 2H). 502II-117

4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide0.11 4 as inExampleII-109 (300 MHZ, CDCl3) δ 8.06(s, 1H), 7.82(m,4H),7.00(m, 2H), 6.72(m, 2H), 5.04(s, 2H), 3.68(m, 2H), 2.88(m, 2H),2.68(m, 4H), 1.86(m, 7H). 502 II-118

4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide0.26 4 as inExampleII-109 (300 MHZ, CDCl3) δ 8.06(s, 1H), 7.82(m,4H),7.00(m, 2H), 6.72(m, 2H), 5.04(s, 2H), 3.75(m, 4H), 3.56(m, 2H),2.62(t, 2H), 2.52(m,4H), 1.83(d, 3H). 518 II-119

N-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzamide0.48 4 as inExampleII-109 (300 MHZ, CDCl3) δ 8.06(s, 1H), 7.82(m,4H),7.00(m, 2H), 6.70(m, 2H), 5.03(s, 2H), 3.62(m, 4H), 3.50(m, 2H),2.65(t, 2H), 2.52(m,4H), 2.10(s, 3H), 1.83(d, 3H). 559 II-120

2-[4-(2-Hydroxy-acetyl)-piperazin-1-yl]-ethanesulfonicacid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide0.19 3 as inExampleI-243 (300 MHZ, CDCl3) δ 7.96(s, 1H), 7.75(d,2H),7.24(m, 3H), 7.08(m, 1H), 6.95(m, 1H), 6.70(q,1H), 5.02(s, 2H),4.14(s, 2H), 3.64(m, 3H), 3.25(m, 4H), 2.91(m, 2H), 2.44(m, 4H), 1.83(d,3H). 611 II-121

3-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzoicacid 3 as inExampleI-211 408 II-122

{3-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone0.19 4 as inExampleII-122 (300 MHZ, CDCl3) δ 8.09(s, 1H), 7.88(m,2H),7.56(m, 1H), 7.44(t, 1H), 7.34(d, 1H), 7.21(t,1H), 5.69(s, 2H),4.92(s, 2H), 4.70(m, 1H),3.82(m, 1H), 3.06(m, 1H), 2.98(m, 1H), 2.65(m,4H), 2.28(m, 1H), 1.02(m, 1H), 1.81(m,5H), 1.55(m, 2H). 544 II-123

3-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-N-{2-[ethyl-(2-methoxy-ethyl)-amino]-ethyl}-benzamide0.45 4 as inExampleII-122 (300 MHZ, CDCl3) δ 8.34(s, 1H), 8.14 (s,1H),8.01(d, 1H), 7.68(d, 1H), 7.53(m, 1H), 7.50(t,1H), 7.45(d, 1H),7.21(t, 1H), 6.79 (bm, 1H),5.72(s, 2H), 4.92(s, 2H), 3.72(m, 4H),3.61(m, 2H), 2.66(m, 2H), 2.55(m, 4H). 520 II-124

{3-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzylloxy)-pyrazin-2-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone0.23 4 as inExampleII-122 (300 MHZ, CDCl3) δ 8.10(s, 1H), 7.90(m,2H),7.60–7.20(m, 5H), 5.70(s, 2H), 4.91(s, 2H),3.85(m, 2H), 3.50(m, 2H),2.52(m, 2H), 2.32(m, 2H), 2.33(s, 3H). 490 II-125

3-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-N-(3-pyrrolidin-1-yl-propyl)-benzamide0.22 4 as inExampleII-122 (300 MHZ, CDCl3) δ 8.85 (bm, 1H), 8.34(s,1H),8.13(s, 1H), 7.95(d, 1H), 7.60(d, 1H), 7.56(m,1H), 7.45(m, 2H),7.20(t, 1H), 5.72(s, 2H),4.92(s, 2H), 3.61(m, 2H), 2.72(m, 2H), 2.57(m,4H), 1.82(m, 2H), 1.76(m, 4H). 518 II-126

N-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-3-[5-amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-benzamide0.65 4 as inExampleII-122 (300 MHZ, CDCl3) δ 8.28(s, 1H), 8.14 (s,1H),7.99(d, 1H), 7.67(d, 1H), 7.58(m, 1H), 7.52(t,1H), 7.42(d, 1H),7.22(t, 1H), 6.75 (bm, 1H),5.72(s, 2H), 4.95(s, 2H), 3.62(m, 4H),3.47(m, 2H), 2.63(m, 2H), 2.52(m, 4H), 2.08(s, 3H). 561 II-127

{4-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone0.047 4 as inExampleII-94 (300 MHZ, CDCl3) δ 8.10(s, 1H), 7.88 (d,2H),7.52(m, 1H), 7.44(d, 2H), 7.42(m, 1H), 7.20(t,1H), 5.71(s, 2H),5.05(s, 2H), 4.62(m, 1H),3.82(m, 1H), 3.06(m, 1H), 2.98(m, 1H), 2.65(m,4H), 2.28(m, 1H), 1.02(m, 1H), 1.81(m,5H), 1.55(m, 2H). 544 II-128

{4-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone0.15 4 as inExampleII-94 (300 MHZ, CDCl3) δ 8.08(s, 1H), 7.88 (d,2H),7.55–7.40(m, 4H), 7.21(t, 1H), 5.72(s, 2H),5.01(s, 2H), 3.82(m, 2H),3.50(m, 2H), 2.50(m, 2H), 2.32(m, 2H), 2.33(s, 3H). 490 II-129

{4-[5-Amino-6-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyrazin-2-yl]-phenyl}-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone0.052 4 as inExampleII-94 (300 MHZ, CDCl3) δ 8.11(s, 1H), 7.88(d,2H),7.68(m, 3H), 7.42(d, 1H), 7.22(t, 1H), 5.72(s,2H), 4.92(s, 2H),3.50(m, 2H), 3.74(m, 4H),1.84(d, 3H), 1.57–2.18(m, 11H). 544 II-130

(3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone0.17 4 as inExampleII-84 (300 MHZ, CDCl3) δ 8.02(s, 1H), 7.79(m,2H),7.40(t, 1H), 7.29(m, 1H), 7.01(t, 1H), 6.81(q,1H), 5.06(s, 2H),3.85(m, 2H), 3.46(m, 2H), 2.51(m, 2H), 2.35(m, 2H), 2.33(s, 3H), 1.84(d,3H). 506 II-131

(3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone0.12 4 as inExampleII-84 (300 MHZ, CDCl3) δ 8.02(s, 1H), 7.78 (m,2H),7.39(t, 1H), 7.24(m, 1H), 7.01(t, 1H), 6.81(q,1H), 5.07(s, 2H),4.71(m, 1H), 3.58(m, 1H),2.96(m, 1H), 2.82(m, 1H), 2.66(m, 1H), 2.42(m,1H), 1.84(d, 3H), 1.74(m, 1H), 1.22(d,3H), 1.00(d, 3H). 518 II-132

3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide0.13 4 as inExampleII-84 (300 MHZ, CD3OD) δ 8.16(s, 1H), 7.99(s,1H),7.82(d, 1H), 7.66(d, 1H), 7.42(m, 2H), 7.15(t,1H), 6.74(q, 1H),3.95(m, 1H), 2.98(m, 2H),2.34(s, 3H), 2.25(m, 2H), 2.01(m, 2H), 1.84(d,3H), 1.73(m, 2H). 520 II-133

3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide0.17 4 as inExampleII-84 (300 MHZ, CD3OD) δ 8.17(s, 1H), 7.99(s,1H),7.82(d, 1H), 7.66(d, 1H), 7.38(m, 2H), 7.12(t,1H), 6.72(q, 1H),3.64(m, 2H), 2.86(m, 2H), 2.75(m, 4H), 2.25(m, 2H), 2.01(m, 2H), 1.84(m,7H). 520 II-134

3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide0.21 4 as inExampleII-84 (300 MHZ, CDCl3) δ 8.13(s, 1H), 8.03(s,1H),7.85(d, 1H), 7.67(d, 1H), 7.42(t, 1H), 7.28(dd,1H), 7.00(t, 1H),6.86(q, 1H), 6.84 (bm, 1H),5.11(s, 2H), 3.72(m, 4H), 3.61(m, 2H),2.63(m, 2H), 2.53(m, 4H), 1.84(d, 3H). 534 II-135

3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-morpholin-4-yl-propyl)-benzamide0.26 4 as inExampleII-84 (300 MHZ, CDCl3) δ 8.19(s, 1H), 8.06(s,1H),7.87(d, 1H), 7.70 (bm, 1H), 7.67(d, 1H), 7.42(t, 1H), 7.28(dd, 1H),7.01(t, 1H), 6.86(q, 1H),5.11(s, 2H), 3.64(m, 6H), 2.54(m, 2H), 2.48(m,4H), 1.84(m, 5H). 548 II-136

(3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-cyclopropylamino-piperidin-1-yl)-methanone0.15 4 as inExampleII-84 544 II-137

3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((S)-2-hydroxy-3-morpholin-4-yl-propyl)-benzamide0.3 4 as inExampleII-84 564 II-138

3-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((R)-2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide0.13 4 as inExampleII-84 548 II-139

(3-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone0.071 4 as inExampleII-84 (300 MHZ, CDCl3) δ 7.86(s, 1H), 7.41 (m,3H),7.30(m, 3H), 7.07(t, 1H), 6.99(s, 1H), 6.12(q,1H), 4.95(s, 2H),4.70(m, 1H), 3.82(m, 1H),3.06(m, 1H), 2.98(m, 1H), 2.65(m, 4H), 2.28(m,1H), 1.02(m, 1H), 1.81(m, 5H), 1.55(m, 2H). 559 II-140

2-Diethylamino-ethanesulfonicacid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide0.35 3 as inExampleI-243 (300 MHZ, CDCl3) δ 7.89(s, 1H), 7.70(d,2H),7.28(m, 2H), 7.21(d, 2H), 7.01(t, 1H), 6.82(q,1H), 5.05(s, 2H),3.22(m, 2H), 3.00(m, 2H),2.55(m, 4H), 1.83(d, 3H), 1.60(d, 6H). 556II-141

2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide0.21 3 as inExampleI-243 (300 MHZ, CDCl3) δ 7.95(s, 1H), 7.71(d,2H),7.28(m, 2H), 7.21(d, 2H), 7.01(t, 1H), 6.82(q,1H), 5.00(s, 2H),3.78(m, 1H), 3.25(t, 2H),2.90(t, 2H), 2.82(m, 2H), 2.25(m, 2H), 1.90(m,2H), 1.84(d, 3H), 1.60(m, 2H). 584 II-142

2-Dimethylamino-ethanesulfonicacid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide0.22 3 as inExampleI-243 (300 MHZ, CDCl3) δ 7.89(s, 1H), 7.70(d,2H),7.28(m, 2H), 7.21(d, 2H), 7.01(t, 1H), 6.82(q,1H), 5.05(s, 2H),3.20(m, 2H), 2.85(m, 2H),2.28(s, 3H), 1.83(d, 3H). 528 II-143

2-((R)-3-Hydroxy-pyrrolidin-1-yl)-ethanesulfonic acid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide0.19 3 as inExampleI-243 (300 MHZ, CDCl3) δ 7.93(s, 1H), 7.69(d,2H),7.27(m, 4H), 7.00(t, 1H), 6.84(q, 1H), 5.03(s,2H), 4.43(m, 1H),3.25(m, 2H), 3.02(m, 3H),2.84(m, 1H), 2.53(m, 1H), 2.30(m, 1H), 2.22(m,1H), 1.84(d, 3H), 1.81(m, 1H). 570 II-144

2-Pyrrolidin-1-ylethanesulfonic acid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide0.36 3 as inExampleI-243 (300 MHZ, CDCl3) δ 7.94(s, 1H), 7.69(d,2H),7.27(m, 2H), 7.19(d, 2H), 7.04(t, 1H), 6.82(q,1H), 5.01(s, 2H),3.28(m, 2H), 3.08(m, 2H),2.60(m, 4H), 1.88(m, 7H). 554 II-145

4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid 1.56 3 as inExampleI-211 422 II-146

4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((R)-2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide0.15 4 as inExampleII-146 548 II-147

(4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-cyclopropylamino-piperidin-1-yl)-methanone0.13 4 as inExampleII-146 544 II-148

4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((S)-2-hydroxy-3-pyrrolidin-1-yl-propyl)-benzamide0.12 4 as inExampleII-146 548 II-149

4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-((R)-2-hydroxy-3-morpholin-4-yl-propyl)-benzamide0.13 4 as inExampleII-146 564 II-150

4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide0.068 4 as inExampleII-146 (300 MHZ, CDCl3) δ 8.01(s, 1H), 7.78(m,4H),7.28(m, 1H), 6.95(t, 1H), 6.80(q, 1H), 5.95(bd, 1H), 5.07(s, 2H),4.05(m, 1H), 2.85(m,2H), 2.32(s, 3H), 2.21(m, 2H), 2.08(m, 2H),1.85(d,3H), 1.68(m, 2H). 518 II-151

(4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone0.18 4 as inExampleII-146 (300 MHZ, CDCl3) δ 8.00(d, 1H), 7.75(d,2H),7.51(d, 2H), 7.28(m, 1H), 7.00(t, 1H), 6.90(q,1H), 5.05(s, 2H),4.45(m, 1H), 3.41(m, 2H),2.70(m, 4H), 1.84(d, 3H), 1.70–2.0(m, 10H) 558II-152

(4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone0.11 4 as inExampleII-146 (300 MHZ, CDCl3) δ 7.00(s, 1H), 7.75(d,2H),7.40(d, 2H), 7.28(m, 1H), 6.99(t, 1H), 6.76(q,1H), 5.04(s, 2H),4.64(m, 1H), 3.84(m, 1H),3.02(m, 2H), 2.60(m, 4H), 2.30(m, 1H), 1.92(m,1H), 1.81(m, 6H), 1.69(m, 2H), 1.62(m, 2H). 558 II-153

4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide0.102 4 as inExampleII-146 (300 MHZ, CDCl3) δ 8.05(s, 1H), 7.79(m,5H),7.25(m, 1H), 6.95(t, 1H), 6.83(q, 1H), 5.10(s,2H), 3.74(m, 4H),3.49(m, 2H), 2.63(m, 2H),2.52(m, 4H), 1.85(d, 3H). 536 II-154

(4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone0.16 4 as inExampleII-146 (300 MHZ, CDCl3) δ 7.99(s, 1H), 7.78(d,2H),7.43(d, 2H), 7.29(m, 1H), 6.85(t, 1H), 6.94(q,1H), 5.07(s, 2H),3.75(m, 2H), 3.50(m, 2H),2.43(m, 4H), 2.33(s, 3H), 1.84(d, 3H). 506II-155

(4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone0.095 4 as inExampleII-146 (300 MHZ, CDCl3) δ 8.02(s, 1H), 7.79(d,2H),7.40(d, 2H), 7.28(m, 1H), 6.98(t, 1H), 6.84(q,1H), 5.04(s, 2H),4.65(m, 1H), 3.56(m, 1H),2.85(m, 2H), 2.70(m, 1H), 2.44(m, 1H), 1.84(d,3H), 1.65(m, 1H), 1.13(m, 3H), 1.00(m, 3H). 518 II-156

4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoic acid3 as inExampleI-211 404 II-157

(4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone0.16 4 as inExampleII-157 (300 MHZ, CDCl3) δ 8.05(s, 1H), 7.82(d,2H),7.50(d, 2H), 7.31(d, 2H), 7.15(t, 1H), 6.90(q,1H), 5.05(s, 2H),2.98(br, 2H), 2.60(s, 4H),2.25(br, 2H), 1.89(d, 3H), 1.2–1.98(br, 8H).540 II-158

4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide0.32 4 as inExampleII-157 (300 MHZ, CDCl3) δ 8.16(s, 1H), 7.89(d,2H),7.75(d, 2H), 7.32(m, 2H), 7.15(t, 1H), 6.91(q,1H), 6.78(m, 1H),5.10(s, 2H), 3.74(m, 4H), 3.63(m, 2H), 2.65(m, 2H), 2.54(m, 4H), 1.85(d,3H). 516 II-159

(4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone0.14 4 as inExampleII-157 (300 MHZ, CDCl3) δ 8.05(s, 1H), 7.82(d,2H),7.50(d, 2H), 7.31(d, 2H), 7.15(t, 1H), 6.90(q,1H), 5.05(s, 2H),4.60(s, 1H), 4.30(t, 1H), 3.60(s, 1H), 2.70(m, 4H), 1.89(d,3H),0.8–1.2(br, 6H). 500 II-160

4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide0.12 4 as inExampleII-157 (300 MHZ, CDCl3) δ 8.16(s, 1H), 7.90(d,2H),7.83(d, 2H), 7.32(t, 2H), 7.16(t, 1H), 6.84(q,1H), 6.00(d, 1H),5.08(s, 2H), 4.05(m, 1H),2.81(m, 2H), 2.35(s, 3H), 2.21(m, 2H), 2.08(m,2H), 1.84(d, 3H), 1.60(m, 2H). 500 II-161

(4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone0.16 4 as inExampleII-157 (300 MHZ, CDCl3) δ 8.05(s, 1H), 7.82(d,2H),7.50(d, 2H), 7.26(d, 2H), 7.15(t, 1H), 6.90(q,1H), 5.05(s, 2H),4.30(t, 1H), 3.50(m, 2H),2.65(m, 4H), 1.86(d, 3H), 1.70–2.0(m, 10H) 542II-162

(4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone0.14 4 as inExampleII-157 (300 MHZ, CDCl3) δ 8.50(s, 1H), 7.82(d,2H),7.50(d, 2H), 7.31(d, 2H), 7.15(t, 1H), 6.90(q,1H), 5.05(s, 2H),4.45(m, 1H), 3.41(m, 2H),2.70(m, 4H), 1.86(d, 3H), 1.70–2.0(m, 10H) 542II-163

(4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone0.15 4 as inExampleII-157 (300 MHZ, CDCl3) δ 8.50(s, 1H), 7.82(d,2H),7.50(d, 2H), 7.31(d, 2H), 7.15(t, 1H), 6.90(q,1H), 5.05(s, 2H),3.60(m, 4H), 2.45(m, 4H),2.31(s, 3H), 1.89(d, 3H) 486 II-164

(4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-3-aminopyrrolidin-1-yl)-methanone0.15 4 as inExampleII-157 (300 MHZ, CD3OD) δ 7.89(m, 3H), 7.60(m,2H),7.40(m, 2H), 7.25(m, 1H), 6.74(m, 1H),4.90(s, 2H), 4.05–3.60(m, 4H),3.50(m, 2H),2.50(m, 1H), 2.18(m, 1H), 1.90(d, 3H). 472 II-165

(4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-3-aminopyrrolidin-1-yl)-methanonehydrogen chloride 0.1 4 as inExampleII-157 (300 MHZ, CD3OD) δ 7.89(m,3H), 7.60(m,2H), 7.40(m, 2H), 7.25(m, 1H), 6.74(m, 1H),4.90(s, 2H),4.05–3.60(m, 4H), 3.50(m, 2H),2.50(m, 1H), 2.18(m, 1H), 1.90(d, 3H). 472II-166

4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide0.11 4 as inExampleII-157 (300 MHZ, CDCl3) δ 8.01(s, 1H), 7.80(m,4H),7.31(dt, 2H), 7.16(t, 1H), 6.84(m, 2H), 5.04(s,2H), 3.55(m, 2H),2.71(m, 2H), 2.57(m, 4H),1.84(d, 3H), 1.83(m, 4H). 502 II-167

4-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide0.22 4 as inExampleII-157 (300 MHZ, CDCl3) δ 8.80(s, 1H), 8.10(s,1H),7.80(m, 4H), 7.21(d, 2H), 7.16(t, 1H), 6.84(q,1H), 5.04(s, 2H),3.55(m, 2H), 2.71(m, 2H), 2.57(m, 4H), 1.84(m, 4H), 1.83(d, 3H), 1.81(m,2H). 514 II-168

3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoic acid3 as inExampleI-211 404 II-169

3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(1-methyl-piperidin-4-yl)-benzamide0.18 4 as inExampleII-169 (300 MHZ, CDCl3) δ 8.16(s, 1H), 8.03(s,1H),7.88(d, 1H), 7.70(d, 1H), 7.42(t, 1H), 7.23(d,2H), 7.10(t, 1H),6.94(q, 1H), 6.15 (bd, 1H),5.08(s, 2H), 4.05(m, 1H), 2.91(m, 2H),2.35(s, 3H), 2.21(m, 2H), 2.08(m, 2H), 1.84(d,3H), 1.68(m, 2H). 502II-170

3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide0.33 4 as inExampleII-169 (300 MHZ, CDCl3) δ 8.15(s, 1H), 8.02(s,1H),7.85(d, 1H), 7.71(d, 1H), 7.40(t, 1H), 7.28(d,2H), 7.10(m, 2H),6.90(q, 1H), 5.10(s, 2H), 3.64(m, 2H), 2.80(m, 2H), 2.64(m, 4H), 1.85(m,7H). 500 II-171

(3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone0.36 4 as inExampleII-169 (300 MHZ, CDCl3) δ 8.04(s, 1H), 7.79(m,2H),7.40(t, 1H), 7.28(m, 3H), 7.11(t, 1H), 6.86(q,1H), 5.05(s, 2H),4.69(m, 1H), 3.56(m, 1H),2.95(m, 1H), 2.79(m, 1H), 2.71(m, 1H), 2.44(m,1H), 1.84(d, 3H), 1.25(d, 3H), 1.17(d, 3H). 500 II-172

3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide0.48 4 as inExampleII-169 (300 MHZ, CDCl3) δ 8.16(s, 1H), 8.03(s,1H),7.89(d, 1H), 7.69(d, 1H), 7.43(t, 1H), 7.28(d,2H), 7.10(t, 1H),6.91(q, 1H), 6.88(m, 1H),5.10(s, 2H), 3.74(m, 4H), 3.63(m, 2H), 2.65(m,2H), 2.54(m, 4H), 1.85(d, 3H). 516 II-173

(3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone0.18 4 as inExampleII-169 (300 MHZ, CDCl3) δ 8.01(d, 1H), 7.87(m,2H),7.37(m, 2H), 7.28(m, 2H), 7.11(t, 1H), 6.90(m, 1H), 5.05(s, 2H),4.45(m, 1H), 3.41(m, 2H),2.70(m, 4H), 1.84(d, 3H), 1.70–2.0(m, 10H) 540II-174

(3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone0.17 4 as inExampleII-169 (300 MHZ, CDCl3) δ 7.99(s, 1H), 7.78(m,2H),7.39(t, 1H), 7.28(m, 3H), 7.08(t, 1H), 6.87(q,1H), 5.04(s, 2H),4.64(m, 1H), 3.84(m, 1H),3.02(m, 2H), 2.60(m, 4H), 2.30(m, 1H), 1.92(m,1H), 1.81(m, 6H), 1.69(m, 2H), 1.62(m, 2H). 540 II-175

N-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-4-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-benzamide0.28 4 as inExampleII-169 (300 MHZ, CDCl3) δ 8.06(s, 1H), 7.89(d,2H),7.75(d, 2H), 7.31(dt, 2H), 7.11(t, 1H), 6.91(q,1H), 6.78(m, 1H),5.12(s, 2H), 4.25(t, 1H),3.60(m, 3H), 3.45(m, 1H), 2.65(t, 2H), 2.50(m,3H), 2.05(s, 2H), 1.85(d, 3H). 559 II-176

N-[2-(4-Acetyl-piperazin-1-yl)-ethyl]-3-{5-amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-benzamide0.35 4 as inExampleII-169 (300 MHZ, CDCl3) δ 8.16(s, 1H), 8.03(s,1H),7.99(d, 1H), 7.69(d, 1H), 7.43(t, 1H), 7.28(d,2H), 7.11(t, 1H),6.91(q, 1H), 6.78(m, 1H),5.12(s, 2H), 3.65(m, 4H), 3.49(m, 2H), 2.68(m,2H), 2.54(m, 4H), 2.09(s, 3H), 1.85(d, 3H). 559 II-177

(3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone0.33 4 as inExampleII-169 (300 MHZ, CDCl3) δ 8.01(d, 1H), 7.87(m,2H),7.37(m, 2H), 7.28(m, 2H), 7.11(t, 1H), 6.90(m, 1H), 5.05(s, 2H),4.45(m, 1H), 3.41(m,2H), 2.70(m, 4H), 1.84(d, 3H), 1.70–2.0(m, 10H) 540II-178

3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide0.34 4 as inExampleII-169 (300 MHZ, CDCl3) δ 8.48(m, 1H), 8.22(t,1H),8.05(s, 1H), 7.91(dt, 1H), 7.66(d, 1H), 7.40(t,1H), 7.28(d, 2H),7.10(t, 1H), 6.94(q, 1H),5.04(s, 2H), 3.62(m, 2H), 2.71(m, 2H), 2.57(m,4H), 1.84(d, 3H), 1.83(m, 2H), 1.81(m, 4H). 514 II-179

(3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((S)-3-amino-pyrroldin-1-yl)-methanone0.11 4 as inExampleII-169 (300 MHZ, CD3OD) δ 7.83(m, 3H), 7.48(m,2H),7.37(m, 2H), 7.23(m, 1H), 6.74(m, 1H),4.05–3.60(m, 4H), 3.50(m, 1H),2.50(m, 1H),2.18(m, 1H), 1.90(d, 3H). 472 II-180

(3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanonehydrochloride salt 0.18 4 as inExampleII-169 (300 MHZ, CD3OD) δ 7.83(m,3H), 7.48(m,2H), 7.37(m, 2H), 7.23(m, 1H), 6.74(m, 1H),4.05–3.60(m, 4H),3.50(m, 1H), 2.50(m, 1H),2.18(m, 1H), 1.90(d, 3H). 472 II-181

(3-{5-Amino-6-[1-(2,6-dichloro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone0.25 4 as inExampleII-169 (300 MHZ, CDCl3) δ 8.00(s, 1H), 7.80(m,2H),7.40(t, 1H), 7.28(m, 3H), 7.11(t, 1H), 6.87(q,1H), 5.05(s, 2H),4.64(m, 1H), 3.87(m, 2H),3.45(m, 2H), 2.53(m, 2H), 2.36(m, 1H), 2.34(s,3H), 1.84(d, 3H). 486 II-182

1-(4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea0.18 10 as inExampleI-371 (300 MHZ, CDCl3) δ 7.93(s, 1H), 7.68(d,2H),7.38(s, 2H), 6.95(m, 4H), 6.70(q, 1H), 4.94(s,2H), 3.75(m, 4H),3.46(m, 2H), 2.69(m, 4H),2.25(m, 2H), 1.85(d, 3H). 534 II-183

(R)-2-Pyrrolidin-1-ylmethyl-pyrrolidin-1-carboxylicacid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide0.21 10 as inExampleI-371 (300 MHZ, CDCl3) δ 7.83(s, 1H), 7.40(d,2H),7.27(d, 2H), 6.95(m, 3H), 5.95(q, 1H), 4.85(s,2H), 3.85(m, 1H),3.75(m, 1H), 3.40(m, 1H),2.90(m, 4H), 2.65(m, 4H), 2.10(m, 3H), 1.85(d,3H), 1.9–1.7(m, 3H). 557 II-184

1-(4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea0.18 10 as inExampleI-371 (300 MHZ, CDCl3) δ 7.91(s, 1H), 7.80 (bs,1H),7.69(d, 2H), 7.46(d, 2H), 7.35 (bm, 1H), 7.05(m, 2H), 6.72(q, 1H),4.86(s, 2H), 3.58(m,2H), 3.19(m, 4H), 3.12(m, 2H), 2.16(m, 4H),2.51(s,3H), 1.81(d, 3H). 517 II-185

4-Methyl-piperazin-1-carboxylic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide0.1 10 as inExampleI-371 (300 MHZ, CDCl3) δ 7.95(s, 1H), 7.69(d,2H),7.39(d, 2H), 7.01–6.91(m, 2H), 6.70(m, 2H),4.90(s, 2H), 3.61(m, 4H),2.58(m, 4H), 2.41(s, 3H), 1.81(d, 3H). 503 II-186

1-(4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-3-(2-hydroxy-ethyl)-urea0.21 10 as inExampleI-371 (300 MHZ, CDCl3) δ 7.78(s, 1H), 7.60(d,2H),7.35(d, 2H), 7.15(m, 4H), 6.55(q, 1H), 4.86(s, 2H), 3.64(t, 2H),3.31(t, 3H), 1.82(d, 3H). 464 II-187

(S)-3-Amino-pyrrolidine-1-carboxylic acid(4-{5-amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide0.082 10 as inExampleI-371 (300 MHZ, CDCl3) δ 7.71(s, 1H), 7.65(d,2H),7.53(d, 2H), 7.15(m, 3H), 6.77(m, 1H), 4.87(s, 2H), 3.95(m, 1H),3.80(m, 1H), 3.65(m,2H), 3.31(m, 2H), 2.57(m, 1H), 2.20(m, 1H),1.95(d,3H). 489 II-188

1-(4-{5-Amino-6-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-3-(1-methyl-piperidin-4-yl)-urea0.054 10 as inExampleI-371 517 II-189

4-Methyl-piperazine-1-carboxylic acid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide0.074 10 as inExampleI-371 (300 MHZ, CDCl3) δ 7.94(s, 1H), 7.66(d,2H),7.37(d, 2H), 7.24(m, 1H), 6.95(t, 1H), 6.81(m,2H), 4.95(s, 2H),3.68(m, 4H), 2.73(m, 4H),2.51(s, 3H), 1.83(d, 3H). 519 II-190

1-(4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-3-(2-hydroxy-ethyl)-urea0.28 10 as inExampleI-371 (300 MHZ, CDCl3) δ 7.84(s, 1H), 7.60(m,4H),7.33(m, 3H), 7.15(m, 1H), 6.70(q, 1H), 4.86(s, 2H), 3.64(t, 2H),3.31(m, 3H), 1.82(d, 3H). 480 II-191

(S)-3-Amino-pyrrolidine-1-carboxylic acid(4-{5-amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-amide3 10 as inExampleI-371 502 II-192

1-(4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-3-(1-methyl-piperidin-4-yl)-urea0.052 10 as inExampleI-371 535 II-193

5-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophene-2-carboxylicacid 3 as inExampleI-270 398 II-194

{5-[Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophen-2-yl}-(4-methyl-piperazin-1-yl)-methanone0.62 4 as inExampleII-194 (300 MHZ, CDCl3) δ 8.01(s, 1H), 7.35(s,1H),7.27(s, 1H), 7.15(m, 1H), 6.98(m, 1H), 5.63(s, 1H), 4.87(m, 1H),3.80(m, 4H), 2.48(m,4H), 2.34(s, 3H). 480 II-195

{5-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophen-2-yl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone0.51 4 as inExampleII-194 (300 MHZ, CDCl3) δ 8.01(s, 1H), 7.35(d,1H),7.24(d, 1H), 7.15(m, 1H), 6.98(m, 1H), 5.63(s, 2H), 4.88(m, 2H),4.42(m, 4H), 3.05(t, 4H),2.63(m, 2H), 2.35(m, 1H), 2.00(m, 2H), 1.82(m,2H), 1.60(m, 2H). 534 II-196

{5-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophen-2-yl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone0.55 4 as inExampleII-194 (300 MHZ, CDCl3) δ 8.01(s, 1H), 7.35(d,1H),7.24(d, 1H), 7.07(m, 1H), 7.01(m, 1H), 5.63(s, 2H), 4.88(m, 2H),4.35(m, 2H), 2.93(m,2H), 2.60(m, 2H), 1.10(d, 6H). 494 II-197

{5-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophen-2-yl}-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone0.8 4 as inExampleII-194 (300 MHZ, CDCl3) δ 8.03(s, 1H), 7.52(d,1H),7.38(d, 1H), 7.07(m, 1H), 7.01(m, 1H), 5.63(s, 2H), 4.88(m, 2H),4.5–0.80(m, 17H). 534 II-198

5-[5-Amino-6-(2-chloro-3,6-difluoro-benzyloxy)-pyrazin-2-yl]-thiophene-2-carboxylicacid(2-morpholin-4-yl-ethyl)-amide 0.7 4 as inExampleII-194 (300 MHZ, CDCl3)δ 8.03(s, 1H), 7.45(d, 1H),7.38(d, 1H), 7.20(m, 1H), 7.05(m, 1H),6.58(m, 1H), 5.65(s, 2H), 4.89(m, 2H), 3.75(m,4H), 3.55(m, 2H), 2.61(m,2H), 2.50(m, 4H) 510 II-199

3-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-{5-[(4-methylpiperazin-1-yl)carbonyl]-pyridin-2-yl}pyrazin-2-aminetrifluoroacetate0.15 4 as inExampleII-194 (DMSO-d6 + TFA/300 MHz) δ 8.64(s, 1H), 8.29(s,1H), 7.96(d, 1H), 7.81(d, 1H), 7.51(m, 1H),7.35(m, 1H), 6.63(q, 1H),4.69–4.25(m, 1H),4.08–3.69(m, 1H), 3.58–3.01(m, 6H), 2.82(s,3H), 1.84(d,3H). 505 II-200

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-pyridin-4-yl-pyrazin-2-ylamine0.045 3 379 II-201

3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-pyrrol-2-yl)-pyrazin-2-ylamine0.22 3 367 II-202

(6-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone0.15 16 as inExampleI-488 505 II-203

(2-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-4-yl)-(4-methyl-piperazin-1-yl)-methanone0.18 16 as inExampleI-488 (DMSO-d6 + TFA/300 MHz) δ 8.68(d, 1H), 8.34(s,1H), 7.62(s, 1H), 7.52–7.27(m, 3H), 6.57(q,1H), 4.66(m, 1H),3.70–2.91(m, 7H), 2.86(s,3H), 1.82(d, 3H). 505 II-204

(6-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone0.22 16 as inExampleI-488 (DMSO-d6 + TFA/300 MHz) δ 8.24(s, 1H),7.96(dd, 1H), 7.79(d, 1H), 7.53(m, 2H), 7.35(dd,1H), 6.61(q, 1H),4.60(br, 1H), 4.12(br, 1H),3.61–3.30(m, 3H), 3.24–3.04(m, 3H),2.83(s,3H), 1.84(d, 3H). 505 II-205

(5-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone0.1 16 as inExampleI-488 (DMSO-d6 + TFA/300 MHz) δ 9.07(s, 1H), 8.77(s,1H), 8.44(s, 1H), 8.31(s, 1H), 7.53(br, 1H),7.44(m, 1H), 7.32(m, 1H),6.58(q, 1H), 4.63(br, 1H), 3.74(br, 1H), 3.61–3.15(m, 4H), 3.06(m, 2H),2.83(s, 3H), 1.81(d, 3H). 505 II-206

(4-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone0.1 16 as inExampleI-488 (DMSO-d6 + TFA/300 MHz) δ 8.63(d, 1H), 8.39(s,1H), 8.01(s, 1H), 7.93(d, 1H), 7.43(m, 1H),7.28(dd, 1H), 6.58(q, 1H),4.63(m, 1H), 3.92(m, 1H), 3.64–3.13(m, 4H), 3.11–2.96(m, 2H),2.84(s,3H), 1.81(d, 3H). 505 II-207

6-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-nicotinamide16 as inExampleI-488 (DMSO-d6 + TFA/300 MHz) δ 9.76 (br, 1H),8.96(m,2H), 8.37(s, 1H), 8.26(d, 1H), 7.80(d,1H), 7.51(m, 1H), 7.37(dd, 1H),6.61(q, 1H),4.00(d, 2H), 3.74–3.50(m, 6H), 3.34(m, 2H),3.16(m, 2H),1.83(d, 3H). 535 II-208

5-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(2-morpholin-4-yl-ethyl)-nicotinamide0.038 16 as inExampleI-488 (DMSO-d6 + TFA/300 MHz) δ 9.16(m, 1H),9.09(s,1H), 9.03(s, 1H), 8.83(s, 1H), 8.28(s,1H), 7.47(m, 1H), 7.32(dd, 1H),6.66(q, 1H),4.00(d, 2H), 3.77–3.50(m, 6H), 3.35(m, 2H),3.16(m, 2H),1.83(d, 3H). 535 II-209

6-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-morpholin-4-yl-propyl)-nicotinamide16 as inExampleI-488 (DMSO-d6 + TFA/300 MHz) δ 9.74(br, 1H), 8.97(s,1H), 8.84(m, 1H), 8.36(s, 1H), 8.26(d, 1H),7.79(d, 1H), 7.50(m, 1H),7.37(dd, 1H), 6.61(q,1H), 3.97(d, 2H), 3.64(t, 2H), 3.50–3.30(m,4H),3.23–2.98(m, 4H), 1.92(m, 2H), 1.83(d, 3H). 549 II-210

5-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-N-(3-morpholin-4-yl-propyl)-nicotinamide0.022 16 as inExampleI-488 (DMSO-d6 + TFA/300 MHz) δ 9.88(br,1H),8.86(s, 1H), 8.30(s, 1H), 7.68–7.40(m, 2H),7.32(m, 1H), 6.67(q, 1H),3.97(d, 2H), 3.66(t,2H), 3.43(m, 4H), 3.25–2.97(m, 4H), 1.96(br,2H),1.83(d, 3H). 549 II-211

(6-{5-Amino-6-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyridin-3-yl)-(4-isopropyl-piperazin-1-yl)-methanone16 as inExampleI-488 (DMSO-d6 + TFA/300 MHz) δ 9.70(br, 1H),8.65(s, 1H),8.38(s, 1H), 7.95(d, 1H), 7.80(d,1H), 7.53(m, 1H) 7.39(dd, 1H), 6.62(q,1H),4.57(br, 1H), 3.85(br, 1H), 3.60–3.05(m, 7H),1.83(d, 3H), 1.26(d,6H). 533

TABLE 5 Section A: Examples L-1 to L-16

% inhibition = 58

% inhibition = 59

% inhibition = 63

% inhibition = 47

% inhibition = 68

% inhibition = 69

% inhibition = 66

% inhibition = 72

% inhibition = 64

% inhibition = 67

% inhibition = 67

% inhibition = 82

% inhibition = 76

% inhibition = 72

% inhibition = 67

% inhibition = 83 Section B: Examples L-17 to L-32

% inhibition = 76

% inhibition = 66

% inhibition = 84

% inhibition = 69

% inhibition = 86

% inhibition = 64

% inhibition = 72

% inhibition = 71

% inhibition = 77

% inhibition = 92

% inhibition = 74

% inhibition = 64

% inhibition = 86

% inhibition = 80

% inhibition = 85

% inhibition = 92 Section C: Examples L-33 to L-48

% inhibition = 63

% inhibition = 62

% inhibition = 55

% inhibition = 62

% inhibition = 75

% inhibition = 86

% inhibition = 77

% inhibition = 55

% inhibition = 84

% inhibition = 55

% inhibition = 85

% inhibition = 55

% inhibition = 84

% inhibition = 78

% inhibition = 83

% inhibition = 67 Section D: Examples L-49 to L-64

% inhibition = 74

% inhibition = 73

% inhibition = 73

% inhibition = 66

% inhibition = 70

% inhibition = 95

% inhibition = 77

% inhibition = 83

% inhibition = 76

% inhibition = 78

% inhibition = 81

% inhibition = 83

% inhibition = 71

% inhibition = 94

% inhibition = 58

% inhibition = 85 Section E: Examples L-65 to L-80

% inhibition = 79

% inhibition = 73

% inhibition = 53

% inhibition = 70

% inhibition = 66

% inhibition = 71

% inhibition = 92

% inhibition = 62

% inhibition = 90

% inhibition = 65

% inhibition = 53

% inhibition = 73

% inhibition = 54

% inhibition = 68

% inhibition = 73

% inhibition = 60 Section F: Examples L-81 to L-96

% inhibition = 67

% inhibition = 74

% inhibition = 54

% inhibition = 67

% inhibition = 86

% inhibition = 57

% inhibition = 56

% inhibition = 90

% inhibition = 96

% inhibition = 85

% inhibition = 69

% inhibition = 64

% inhibition = 62

% inhibition = 51

% inhibition = 65

% inhibition = 61 Section G: Examples L-97 to L-112

% inhibition = 60

% inhibition = 73

% inhibition = 83

% inhibition = 77

% inhibition = 79

% inhibition = 82

% inhibition = 91

% inhibition = 89

% inhibition = 81

% inhibition = 89

% inhibition = 87

% inhibition = 70

% inhibition = 76

% inhibition = 71

% inhibition = 71

% inhibition = 85 Section H: Examples L-113 to L-128

% inhibition = 57

% inhibition = 56

% inhibition = 63

% inhibition = 62

% inhibition = 60

% inhibition = 86

% inhibition = 59

% inhibition = 63

% inhibition = 75

% inhibition = 61

% inhibition = 80

% inhibition = 69

% inhibition = 77

% inhibition = 52

% inhibition = 56

% inhibition = 64 Section I: Examples L-129 to L-144

% inhibition = 82

% inhibition = 60

% inhibition = 61

% inhibition = 65

% inhibition = 68

% inhibition = 76

% inhibition = 76

% inhibition = 61

% inhibition = 78

% inhibition = 83

% inhibition = 60

% inhibition = 64

% inhibition = 79

% inhibition = 72

% inhibition = 59

% inhibition = 71 Section J: Examples L-145 to L-160

% inhibition = 77

% inhibition = 89

% inhibition = 96

% inhibition = 62

% inhibition = 70

% inhibition = 81

% inhibition = 58

% inhibition = 53

% inhibition = 95

% inhibition = 77

% inhibition = 66

% inhibition = 73

% inhibition = 77

% inhibition = 63

% inhibition = 78

% inhibition = 59 Section K: Examples L-161 to L-176

% inhibition = 79

% inhibition = 66

% inhibition = 83

% inhibition = 61

% inhibition = 88

% inhibition = 67

% inhibition = 66

% inhibition = 90

% inhibition = 79

% inhibition = 77

% inhibition = 69

% inhibition = 79

% inhibition = 63

% inhibition = 68

% inhibition = 60

% inhibition = 51

TABLE 6 Section A: Examples L-177 to L-192

% Inhibition = 26

% Inhibition = 30

% Inhibition = 24

% Inhibition = 26

% Inhibition = 31

% Inhibition = 27

% Inhibition = 32

% Inhibition = 27

% Inhibition = 29

% Inhibition = 30

% Inhibition = 30

% Inhibition = 39

% Inhibition = 35

% Inhibition = 35

% Inhibition = 38

% Inhibition = 44 Section B: Examples L-193 to L-208

% Inhibition = 37

% Inhibition = 35

% Inhibition = 37

% Inhibition = 34

% Inhibition = 36

% Inhibition = 59

% Inhibition = 33

% Inhibition = 31

% Inhibition = 30

% Inhibition = 33

% Inhibition = 33

% Inhibition = 51

% Inhibition = 32

% Inhibition = 32

% Inhibition = 33

% Inhibition = 27 Section C: Examples L-209 to L-224

% Inhibition = 31

% Inhibition = 39

% Inhibition = 31

% Inhibition = 36

% Inhibition = 31

% Inhibition = 49

% Inhibition = 33

% Inhibition = 29

% Inhibition = 34

% Inhibition = 35

% Inhibition = 34

% Inhibition = 32

% Inhibition = 29

% Inhibition = 26

% Inhibition = 29

% Inhibition = 30 Section D: Examples L-225 to L-240

% Inhibition = 33

% Inhibition = 24

% Inhibition = 83

% Inhibition = 24

% Inhibition = 24

% Inhibition = 23

% Inhibition = 62

% Inhibition = 44

% Inhibition = 32

% Inhibition = 34

% Inhibition = 36

% Inhibition = 33

% Inhibition = 30

% Inhibition = 35

% Inhibition = 34

% Inhibition = 30 Section E: Examples L-241 to L-256

% Inhibition = 30

% Inhibition = 66

% Inhibition = 32

% Inhibition = 33

% Inhibition = 33

% Inhibition = 28

% Inhibition = 25

% Inhibition = 27

% Inhibition = 32

% Inhibition = 37

% Inhibition = 29

% Inhibition = 32

% Inhibition = 28

% Inhibition = 45

% Inhibition = 45

% Inhibition = 46 Section F: Examples L-257 to L-272

% Inhibition = 43

% Inhibition = 45

% Inhibition = 39

% Inhibition = 40

% Inhibition = 40

% Inhibition = 42

% Inhibition = 36

% Inhibition = 38

% Inhibition = 17

% Inhibition = 10

% Inhibition = 5

% Inhibition = 15

% Inhibition = 10

% Inhibition = 2

% Inhibition = 16

% Inhibition = 15 Section G: Examples L-273 to L-288

% Inhibition = 17

% Inhibition = 19

% Inhibition = 28

% Inhibition = 32

% Inhibition = 26

% Inhibition = 31

% Inhibition = 32

% Inhibition = 56

% Inhibition = 26

% Inhibition = 22

% Inhibition = 26

% Inhibition = 27

% Inhibition = 31

% Inhibition = 47

% Inhibition = 21

% Inhibition = 20 Section G: Examples L-289 to L-304

% Inhibition = 24

% Inhibition = 19

% Inhibition = 26

% Inhibition = 99

% Inhibition = 16

% Inhibition = 20

% Inhibition = 18

% Inhibition = 23

% Inhibition = 26

% Inhibition = 31

% Inhibition = 25

% Inhibition = 22

% Inhibition = 24

% Inhibition = 41

% Inhibition = 24

% Inhibition = 18 Section I: Examples L-305 to L-320

% Inhibition = 26

% Inhibition = 22

% Inhibition = 22

% Inhibition = 33

% Inhibition = 16

% Inhibition = 16

% Inhibition = 17

% Inhibition = 19

% Inhibition = 10

% Inhibition = 16

% Inhibition = 72

% Inhibition = 11

% Inhibition = 12

% Inhibition = 17

% Inhibition = 71

% Inhibition = 28 Section J: Examples L-321 to L-336

% Inhibition = 25

% Inhibition = 25

% Inhibition = 26

% Inhibition = 25

% Inhibition = 26

% Inhibition = 3

% Inhibition = 26

% Inhibition = 27

% Inhibition = 30

% Inhibition = 74

% Inhibition = 23

% Inhibition = 21

% Inhibition = 23

% Inhibition = 17

% Inhibition = 18

% Inhibition = 20 Section K: Examples L-337 to L-352

% Inhibition = 20

% Inhibition = 21

% Inhibition = 18

% Inhibition = 19

% Inhibition = 20

% Inhibition = 36

% Inhibition = 37

% Inhibition = 41

% Inhibition = 45

% Inhibition = 31

% Inhibition = 38

% Inhibition = 35

% Inhibition = 32

% Inhibition = 34

% Inhibition = 35

% Inhibition = 47

TABLE 7 Section A: Examples L-353 to L-368

% Inhibition = 24

% Inhibition = 19

% Inhibition = 32

% Inhibition = 22

% Inhibition = 20

% Inhibition = 14

% Inhibition = 24

% Inhibition = 10

% Inhibition = 8

% Inhibition = 37

% Inhibition = 36

% Inhibition = 6

% Inhibition = 8

% Inhibition = 9

% Inhibition = 6

% Inhibition = 27 Section B: Examples L-369 to L-384

% Inhibition = 10

% Inhibition = 19

% Inhibition = 10

% Inhibition = 49

% Inhibition = 19

% Inhibition = 5

% Inhibition = 10

% Inhibition = 10

% Inhibition = 19

% Inhibition = 34

% Inhibition = 40

% Inhibition = 26

% Inhibition = 26

% Inhibition = 9

% Inhibition = 14

% Inhibition = 9 Section C: Examples L-385 to L-400

% Inhibition = 10

% Inhibition = 13

% Inhibition = 8

% Inhibition = 24

% Inhibition = 14

% Inhibition = 15

% Inhibition = 15

% Inhibition = 28

% Inhibition = 26

% Inhibition = 12

% Inhibition = 15

% Inhibition = 12

% Inhibition = 30

% Inhibition = 10

% Inhibition = 28

% Inhibition = 21 Section D: Examples L-401 to L-416

% Inhibition = 9

% Inhibition = 11

% Inhibition = 4

% Inhibition = 41

% Inhibition = 21

% Inhibition = 14

% Inhibition = 13

% Inhibition = 12

% Inhibition = 31

% Inhibition = 19

% Inhibition = 27

% Inhibition = 25

% Inhibition = 31

% Inhibition = 45

% Inhibition = 11

% Inhibition = 77 Section E: Examples L-417 to L-432

% Inhibition = 11

% Inhibition = 9

% Inhibition = 12

% Inhibition = 7

% Inhibition = 10

% Inhibition = 14

% Inhibition = 10

% Inhibition = 12

% Inhibition = 13

% Inhibition = 11

% Inhibition = 10

% Inhibition = 11

% Inhibition = 13

% Inhibition = 11

% Inhibition = 10

% Inhibition = 18 Section F: Examples L-433 to L-448

% Inhibition = 23

% Inhibition = 47

% Inhibition = 15

% Inhibition = 24

% Inhibition = 32

% Inhibition = 19

% Inhibition = 21

% Inhibition = 59

% Inhibition = 20

% Inhibition = 26

% Inhibition = 24

% Inhibition = 26

% Inhibition = 21

% Inhibition = 18

% Inhibition = 14

% Inhibition = 15 Section G: Examples L-449 to L-464

% Inhibition = 15

% Inhibition = 17

% Inhibition = 12

% Inhibition = 15

% Inhibition = 13

% Inhibition = 13

% Inhibition = 33

% Inhibition = 11

% Inhibition = 17

% Inhibition = 15

% Inhibition = 31

% Inhibition = 23

% Inhibition = 22

% Inhibition = 12 Section H: Examples L-465 to L480

% Inhibition = 14

% Inhibition = 18

% Inhibition = 13

% Inhibition = 13

% Inhibition = 10

% Inhibition = 9

% Inhibition = 10

% Inhibition = 9

% Inhibition = 50

% Inhibition = 39

% Inhibition = 51

% Inhibition = 27

% Inhibition = 29

% Inhibition = 24

% Inhibition = 15

% Inhibition = 17 Section I: Examples L-481 to L496

% Inhibition = 16

% Inhibition = 20

% Inhibition = 19

% Inhibition = 16

% Inhibition = 18

% Inhibition = 22

% Inhibition = 63

% Inhibition = 17

% Inhibition = 18

% Inhibition = 23

% Inhibition = 16

% Inhibition = 22

% Inhibition = 14

% Inhibition = 18

% Inhibition = 14

% Inhibition = 14 Section J: Examples L-497 to L-512

% Inhibition = 34

% Inhibition = 24

% Inhibition = 19

% Inhibition = 19

% Inhibition = 18

% Inhibition = 19

% Inhibition = 17

% Inhibition = 16

% Inhibition = 17

% Inhibition = 17

% Inhibition = 20

% Inhibition = 12

% Inhibition = 16

% Inhibition = 23

% Inhibition = 16

% Inhibition = 16 Section K: Examples L-513 to L-528

% Inhibition = 16

% Inhibition = 17

% Inhibition = 17

% Inhibition = 16

% Inhibition = 19

% Inhibition = 15

% Inhibition = 8

% Inhibition = 14

% Inhibition = 23

% Inhibition = 7

% Inhibition = 9

% Inhibition = 5

% Inhibition = 5

% Inhibition = 10

% Inhibition = 9

% Inhibition = 9 Section L: Examples L-529 to L-548

% Inhibition = 9

% Inhibition = 8

% Inhibition = 8

% Inhibition = 27

% Inhibition = 12

% Inhibition = 18

% Inhibition = 4

% Inhibition = 16

% Inhibition = 12

% Inhibition = −2

% Inhibition = 28

% Inhibition = 11

% Inhibition = 5

% Inhibition = 6

% Inhibition = 7

% Inhibition = 8

% Inhibition = 11

% Inhibition = 11

% Inhibition = 64

% Inhibition = 18

TABLE 8 Section A: Examples L-549 to L-561

% Inhibition = 11

% Inhibition = 13

% Inhibition = 11

% Inhibition = 20

% Inhibition = 25

% Inhibition = 14

% Inhibition = 21

% Inhibition = 12

% Inhibition = 40

% Inhibition = 27

% Inhibition = 32

% Inhibition = 16

% Inhibition = 16

% Inhibition = 17

% Inhibition = 7 

% Inhibition = 21 Section B: Examples L-565 to L-580

% Inhibition = 28

% Inhibition = 29

% Inhibition = 20

% Inhibition = 25

% Inhibition = 22

% Inhibition = 41

% Inhibition = 28

% Inhibition = 17

% Inhibition = 19

% Inhibition = 33

% Inhibition = 11

% Inhibition = 24

% Inhibition = 24

% Inhibition = 29

% Inhibition = 42

% Inhibition = 73 Section C: Examples L-581 to L-596

% Inhibition = 19

% Inhibition = 17

% Inhibition = 14

% Inhibition = 9 

% Inhibition = 30

% Inhibition = 6 

% Inhibition = 26

% Inhibition = 32

% Inhibition = 15

% Inhibition = 18

% Inhibition = 18

% Inhibition = 19

% Inhibition = 12

% Inhibition = 10

% Inhibition = 8 

% Inhibition = 19 Section D: Examples L-597 to L-612

% Inhibition = 28

% Inhibition = 17

% Inhibition = 58

% Inhibition = 25

% Inhibition = 17

% Inhibition = 17

% Inhibition = 20

% Inhibition = 12

% Inhibition = 14

% Inhibition = 14

% Inhibition = 17

% Inhibition = 19

% Inhibition = 16

% Inhibition = 35

% Inhibition = 25

% Inhibition = 13 Section E: Examples L-613 to L-628

% Inhibition = 13

% Inhibition = 16

% Inhibition = 15

% Inhibition = 51

% Inhibition = 37

% Inhibition = 35

% Inhibition = 16

% Inhibition = 28

% Inhibition = 21

% Inhibition = 16

% Inhibition = 17

% Inhibition = 18

% Inhibition = 14

% Inhibition = 16

% Inhibition = 12

% Inhibition = 13 Section F: Examples L-629 to L-636

% Inhibition = 27

% Inhibition = 15

% Inhibition = 10

% Inhibition = 13

% Inhibition = 13

% Inhibition = 14

% Inhibition = 29

% Inhibition = 13

The present invention is not to be limited in scope by the exemplifiedaspects which are intended as illustrations of single aspects of theinvention, and any clones, DNA or amino acid sequences which arefunctionally equivalent are within the scope of the invention. Indeed,various modifications of the invention in addition to those describedherein will become apparent to those skilled in the art from theforegoing description and accompanying drawings. Such modifications areintended to fall within the scope of the appended claims.

The disclosure of U.S. Provisional Application Ser. No. 60/449,588,filed Feb. 26, 2003, and U.S. Provisional Application Ser. No.60/540,229, filed Jan. 29, 2004, are hereby incorporated by reference intheir entireties.

All references cited herein are hereby incorporated by reference intheir entireties.

1. A compound of formula 1

wherein: Y is CR¹²; R¹ is selected from C₆₋₁₂ aryl, 5–12 memberedheteroaryl, C₃₋₁₂ cycloalkyl, 3–12 membered heteroalicyclic; and eachhydrogen in R¹ is optionally substituted by one or more R³ groups; R² ishydrogen; R³ is halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12membered heteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁶)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴S(O)_(p)R⁵ or —C(O)NR⁴R⁵, each hydrogen in R³ is optionallysubstituted by one or more R⁸ groups, and R³ groups on adjacent atomsmay combine to form a C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂cycloalkyl, or 3–12 membered heteroalicyclic group; each R⁴, R⁵, R⁶ andR⁷ is independently hydrogen, halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic,5–12 membered heteroaryl; or any two of R⁴, R⁵, R⁶ and R⁷ bound to thesame nitrogen atom may, together with the nitrogen to which they arebound, be combined to form a 3 to 12 membered heteroalicyclic or 5–12membered heteroaryl group optionally containing 1 to 3 additionalheteroatoms selected from N, O, and S; or any two of R⁴, R⁵, R⁶ and R⁷bound to the same carbon atom may be combined to form a C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic or 5–12 memberedheteroaryl group; and each hydrogen in R⁴, R⁵, R⁶ and R⁷ is optionallysubstituted by one or more R⁸ groups; each R⁸ is independently halogen,C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl,3–12 membered heteroalicyclic, 5–12 membered heteroaryl, —CN, —O—C₁₋₁₂alkyl, —O—(CH₂)_(n)C₃₋₁₂ cycloalkyl, —O—(CH₂)_(n)C₆₋₁₂ aryl,—O—(CH₂)_(n)(3–12 membered heteroalicyclic) or —O—(CH₂)_(n)(5–12membered heteroaryl); and each hydrogen in R⁸ is optionally substitutedby one or more R¹¹ groups; A¹ is (CR⁹R¹⁰)_(n)-A² each R⁹ and R¹⁰ isindependently hydrogen, halogen, C₁₋₁₂ alkyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂aryl, 3–12 membered heteroalicyclic, 5–12 membered heteroaryl,—S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵, —(CR⁶R⁷)_(n)OR⁴, —CN,—C(O)R⁴, —OC(O)R⁴, —NR⁴C(O)R⁵, —(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵,—NR⁴C(O)NR⁵R⁶, —NR⁴S(O)_(p)R⁵ or —C(O)NR⁴R⁵; R⁹ and R¹⁰ may combine toform a C₃₋₁₂ cycloalkyl, 3–12 membered heteroalicyclic, C₆₋₁₂ aryl or5–12 membered heteroaryl ring; and each hydrogen in R⁹ and R¹⁰ isoptionally substituted by one or more R³ groups; A² is C₆₋₁₂ aryl, 5–12membered heteroaryl, C₃₋₁₂ cycloalkyl or 3–12 membered heteroalicyclic,and A² is optionally substituted by one or more R³ groups; each R¹¹ isindependently halogen, C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₃₋₁₂ cycloalkyl,C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 membered heteroaryl,—O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂ cycloalkyl, —O—(CH₂)_(n)C₆₋₁₂ aryl,—O—(CH₂)_(n)(3–12 membered heteroalicyclic), —O—(CH₂)_(n)(5–12 memberedheteroaryl) or —CN, and each hydrogen in R¹¹ is optionally substitutedby one or more groups selected from halogen, —OH, —CN, —C₁₋₁₂ alkylwhich may be partially or fully halogenated, —O—C₁₋₁₂ alkyl which may bepartially or fully halogenated, —CO, —SO and —SO₂; R¹² is hydrogen; m is0, 1 or 2; n is 0, 1, 2, 3 or 4; and p is 1 or 2; wherein said 3–12membered heteroalicyclic group is selected from pyrroline, pyrrolidine,dioxolane, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran,piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazineand trithiane and said 5–12 membered heteroaryl group is selected fromfuran, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole,isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyridine,pyridazine, pyrimidine, pyrazine and triazine; or a pharmaceuticallyacceptable salt, or hydrate thereof.
 2. The compound of claim 1, whereinthe compound has formula 1a

wherein A² is C₆₋₁₂ aryl or 5–12 membered heteroaryl optionallysubstituted by one or more R³ groups.
 3. The compound of claim 2,wherein R¹ is selected from C₆₋₁₂ aryl and 5–12 membered heteroaryl, andeach hydrogen in R¹ is optionally substituted by one or more R³ groups.4. The compound of claim 2, wherein A² is substituted by at least onehalogen atom.
 5. The compound of claim 1, wherein R¹ is a furan,thiopene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole,imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline,pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole,pyran, pyridine, piperidine, dioxane, morpholine, dithiane,thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine,trithiane or phenyl group, and each hydrogen in R¹ is optionallysubstituted by one or more R³ groups.
 6. A compound of formula 2

wherein: R¹ is selected from C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂cycloalkyl, 3–12 membered heteroalicyclic; and each hydrogen in R¹ isoptionally substituted by one or more R³ groups; R² is hydrogen; R³ ishalogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl,C₆₋₁₂-aryl, 3–12 membered heteroalicyclic, 5–12 membered heteroaryl,—S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵, —(CR⁶R⁷)_(n)OR⁴, —CN,—C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴, —NR⁴C(O)R⁵, —(CR⁶R⁷)_(n)C(O)OR⁴,—(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁶)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴S(O)_(p)R⁵ or—C(O)NR⁴R⁵, each hydrogen in R³ is optionally substituted by one or moreR⁸ groups, and R³ groups on adjacent atoms may combine to form a C₆₋₁₂aryl, 5–12 membered heteroaryl, C₃₋₁₂ cycloalkyl or 3–12 memberedheteroalicyclic group; each R⁴, R⁵, R⁶ and R⁷ is independently hydrogen,halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl,C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 membered heteroaryl; orany two of R⁴, R⁵, R⁶ and R⁷ bound to the same nitrogen atom may,together with the nitrogen to which they are bound, be combined to forma 3 to 12 membered heteroalicyclic or 5–12 membered heteroaryl groupoptionally containing 1 to 3 additional heteroatoms selected from N, O,and S; or any two of R⁴, R⁵, R⁶ and R⁷ bound to the same carbon atom maybe combined to form a C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 memberedheteroalicyclic or 5–12 membered heteroaryl group; and each hydrogen inR⁴, R⁵, R⁶ and R⁷ is optionally substituted by one or more R⁸ groups;each R⁸ is independently halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic,5–12 membered heteroaryl, —CN, —O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂cycloalkyl, —O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3–12 memberedheteroalicyclic) or —O—(CH₂)_(n)(5–12 membered heteroaryl); and eachhydrogen in R⁸ is optionally substituted by one or more R¹¹ groups; A¹is —(CR⁹R¹⁰)_(n)-A²; each R⁹ and R¹⁰ is independently hydrogen, halogen,C₁₋₁₂ alkyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 memberedheteroalicyclic, 5–12 membered heteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵,—S(O)₂OR⁴, —NO₂, —NR⁴R⁵, —(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴,—NR⁴C(O)R⁵, —(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴S(O)_(p)R⁵ or —C(O)NR⁴R⁵; R⁹ and R¹⁰ may combine to form a C₃₋₁₂cycloalkyl, 3–12 membered heteroalicyclic, C₆₋₁₂ aryl or 5–12 memberedheteroaryl ring; and each hydrogen in R⁹ and R¹⁰ is optionallysubstituted by one or more R³ groups; A² is C₆₋₁₂ aryl, 5–12 memberedheteroaryl, C₃₋₁₂ cycloalkyl or 3–12 membered heteroalicyclic, and A² isoptionally substituted by one or more R³ groups; each R¹¹ isindependently halogen, C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₃₋₁₂ cycloalkyl,C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 membered heteroaryl,—O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂ cycloalkyl, —O—(CH₂)_(n)C₆₋₁₂ aryl,—O—(CH₂)_(n)(3–12 membered heteroalicyclic), —O—(CH₂)_(n)(5–12 memberedheteroaryl) or —CN, and each hydrogen in R¹¹ is optionally substitutedby one or more groups selected from halogen, —OH, —CN, —C₁₋₁₂ alkylwhich may be partially or fully halogenated, —O—C₁₋₁₂ alkyl which may bepartially or fully halogenated, —CO, —SO and —SO₂; R¹² is hydrogen; m is0, 1 or 2; n is 0, 1, 2, 3 or 4; and p is 1 or 2; wherein said 3–12membered heteroalicyclic group is selected from pyrroline, pyrrolidine,dioxolane, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran,piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazineand trithiane and said 5–12 membered heteroaryl group is selected fromfuran, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole,isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyridine,pyridazine, pyrimidine, pyrazine and triazine; or a pharmaceuticallyacceptable salt, or hydrate thereof.
 7. The compound of claim 6, whereinthe compound has formula 2a

wherein A² is C₆₋₁₂ aryl or 5–12 membered heteroaryl optionallysubstituted by one or more R³ groups.
 8. The compound of claim 7,wherein R¹ is selected from C₆₋₁₂ aryl and 5–12 membered heteroaryl, andeach hydrogen in R¹ is optionally substituted by one or more R³ groups.9. The compound of claim 7, wherein A² is substituted by at least onehalogen atom.
 10. The compound of claim 6, wherein R¹ is a furan,thiopene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole,imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline,pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole,pyran, pyridine, piperidine, dioxane, morpholine, dithiane,thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine,trithiane or phenyl group, and each hydrogen in R¹ is optionallysubstituted by one or more R³ groups.
 11. A compound of formula 4

wherein: R¹ is selected from C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂cycloalkyl, 3–12 membered heteroalicyclic; and each hydrogen in R¹ isoptionally substituted by one or more R³ groups; R³ is halogen, C₁₋₁₂alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12membered heteroalicyclic, 5–12 membered heteroaryl, —S(O)_(m)R⁴,—SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵, —(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴,—OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴, —NR⁴C(O)R⁵, —(CR⁶R⁷)_(n)C(O)OR⁴,—(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁶)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴S(O)_(p)R⁵ or—C(O)NR⁴R⁵, each hydrogen in R³ is optionally substituted by one or moreR⁸ groups, and R³ groups on adjacent atoms may combine to form a C₆₋₁₂aryl, 5–12 membered heteroaryl, C₃₋₁₂ cycloalkyl or 3–12 memberedheteroalicyclic group; each R⁴, R⁵, R⁶ and R⁷ is independently hydrogen,halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl,C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 membered heteroaryl; orany two of R⁴, R⁵, R⁶ and R⁷ bound to the same nitrogen atom may,together with the nitrogen to which they are bound, be combined to forma 3 to 12 membered heteroalicyclic or 5–12 membered heteroaryl groupoptionally containing 1 to 3 additional heteroatoms selected from N, O,and S; or any two of R⁴, R⁵, R⁶ and R⁷ bound to the same carbon atom maybe combined to form a C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 memberedheteroalicyclic or 5–12 membered heteroaryl group; and each hydrogen inR⁴, R⁵, R⁶ and R⁷ is optionally substituted by one or more R⁸ groups;each R⁸ is independently halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic,5–12 membered heteroaryl, —CN, —O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂cycloalkyl, —O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3–12 memberedheteroalicyclic) or —O—(CH₂)_(n)(5–12 membered heteroaryl); and eachhydrogen in R⁸ is optionally substituted by one or more R¹¹ groups; eachR⁹ and R¹⁰ is independently hydrogen, halogen, C₁₋₁₂ alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3–12 membered heteroalicyclic, 5–12 memberedheteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴S(O)_(p)R⁵or —C(O)NR⁴R⁵; R⁹ and R¹⁰ may combine to form a C₃₋₁₂ cycloalkyl, 3–12membered heteroalicyclic, C₆₋₁₂ aryl or 5–12 membered heteroaryl ring;and each hydrogen in R⁹ and R¹⁰ is optionally substituted by one or moreR³ groups; A² is C₆₋₁₂ aryl, 5–12 membered heteroaryl, C₃₋₁₂ cycloalkylor 3–12 membered heteroalicyclic, and A² is optionally substituted byone or more R³ groups; each R¹¹ is independently halogen, C₁₋₁₂ alkyl,C₁₋₁₂ alkoxy, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3–12 memberedheteroalicyclic, 5–12 membered heteroaryl, —O—C₁₋₁₂ alkyl,—O—(CH₂)_(n)C₃₋₁₂ cycloalkyl, —O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3–12membered heteroalicyclic), —O—(CH₂)_(n)(5–12 membered heteroaryl) or—CN, and each hydrogen in R¹¹ is optionally substituted by one or moregroups selected from halogen, —OH, —CN, —C₁₋₁₂ alkyl which may bepartially or fully halogenated, —O—C₁₋₁₂ alkyl which may be partially orfully halogenated, —CO, —SO and —SO₂; m is 0, 1 or 2; n is 0, 1, 2, 3 or4; and p is 1 or 2; wherein said 3–12 membered heteroalicyclic group isselected from pyrroline, pyrrolidine, dioxolane, imidazoline,imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, dioxane,morpholine, dithiane, thiomorpholine, piperazine and trithiane and said5–12 membered heteroaryl group is selected from furan, thiophene,pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole,oxadiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine,pyrazine and triazine; or a pharmaceutically acceptable salt, or hydratethereof.
 12. The compound of claim 11, wherein A² is C₆₋₁₂ aryl or 5–12membered heteroaryl optionally substituted by one or more R³ groups. 13.A compound of formula 6

wherein, Z is CR or N; Aryl is an optionally fused aryl or an optionallyfused heteroaryl group which is optionally substituted by one or moresubstituents selected from the group consisting of a halogen, —OR²⁴,COR²⁴, —COOR²⁴, —CONR²⁴R²⁵, —CN, —NO₂, —S(O)_(m)R²⁴, —SO₂NR²⁴R²⁵,perfluoroalkyl, lower alkyl, cycloalkyl, heterocycle, alkenyl, alkynyl,aryl, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵ and —NR²⁴S(O)_(p)R²⁵; R²¹ and R²² areindependently selected from the group consisting of hydrogen, halogen,—COR²⁴, —COOR²⁴, —CONR²⁴R²⁵, —CN, perfluoroalkyl, lower alkyl,cycloalkyl, heterocycle, alkenyl, alkynyl, and aryl; R²³ is selectedfrom the group consisting of: an optionally fused aryl, heteroaryl,alicyclic or heterocyclic group, optionally substituted by one or moresubstituents selected from the group consisting of a halogen,—(CH₂)_(n)—OR²⁴, COR²⁴, —COOR²⁴, —CONR²⁴R²⁵, —CN, —NO₂, —S(O)_(m)R²⁴,—SO₂NR²⁴R²⁵, perfluoroalkyl, —O-perfluoroalkyl, lower alkyl, cycloalkyl,heterocycle, heteroaryl, alkenyl, alkynyl, aryl, —(CH₂)_(n)—NR²⁴R²⁵,—NR²⁴C(O)R²⁵ and —NR²⁴S(O)_(p)R²⁵, wherein said heterocycle, heteroaryland aryl substituents may be optionally substituted by a group selectedfrom the group consisting of lower alkyl, halogen, —C(O)NR²⁴R²⁵,NR²⁴R²⁵, NR²⁴C(O)R²⁵ and NR²⁴S(O)_(p)R²⁵; —OR²⁴, —COR²⁴, —COOR²⁴, —CN,—NO₂, —S(O)_(m)R²⁴, —SO₂NR²⁴R²⁵, perfluoroalkyl, cycloalkyl,heterocycle, alkenyl, and alkynyl; R²⁴ and R²⁵ are independentlyselected from the group consisting of hydrogen, lower alkyl, cycloalkyl,alkenyl, alkynyl, aryl, aminoalkyl, alkylaminoalkyl,alkylaminocycloalkyl, dialkylaminoalkyl and —(CH₂)_(n)-heterocycle,wherein said —(CH₂)_(n)-heterocycle may be further substituted by one ormore of lower alkyl, —(CH₂)_(n)-hydroxy, heterocycle and —C(O)R²⁶, orR²⁴ and R²⁵ can combine to form a 5- to 6-membered heterocyclic ringhaving one or more heteroatoms selected from the group consisting of N,O, S, S(O) and SO₂, said 5- to 6-membered heterocyclic ring may beoptionally substituted by lower alkyl, —(CH₂)_(n)-heterocycle,cycloalkyl, halo, —(CH₂)_(n)—NR²⁶R²⁷, amino, —C(O)R²⁶, —NR²⁶—(O)OR²⁷ and—NR²⁶—C(O)R²⁷; wherein R²⁶ and R²⁷ are independently selected from thegroup consisting of hydrogen, lower alkyl, —(CH₂)_(n)-cycloalkyl and—C(O)—(CH₂)_(n)—OH; except that when Z is N and R²¹ and R²² are H andAryl is m-chlorophenyl, R²³ is not piperazine; m is 0, 1 or 2; n is 0,1, 2 or 3; p is 1 or 2; wherein said heterocyclic group is selected frompyrroline, pyrrolidine, dioxolane, imidazoline, imidazolidine,pyrazoline, pyrazolidine, pyran, piperidine, dioxane, morpholine,dithiane, thiomorpholine, piperazine and trithiane and said heteroarylgroup is selected from furan, thiophene, pyrrole, oxazole, thiazole,imidazole, pyrazole, isoxazole, isothiazole, oxadiazole, triazole,thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine; ora pharmaceutically acceptable salt thereof.
 14. The compound of claim13, wherein R²³ is aryl or heteroaryl.
 15. A compound selected from thegroup consisting of:(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzamide;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}—N-(3-pyrrolidin-1-yl-propyl)-benzamide;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-amino-piperidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-hydroxy-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone;(4-(6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-diethylamino-ethyl)-benzamide;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzamide;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-morpholin-4-yl-propyl)-benzamide;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;2-diethylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-(4-Hydroxy-piperidin-1-yl)-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-piperidin-1-yl-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-(cyclopropylmethyl-amino)-ethanesulfonic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-((R)-3-Hydroxy-pyrrolidin-1-yl)-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-cyclopropylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;2-diethylamino-ethanesulfonic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid;4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxyl]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone;3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid;(3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;(3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone;3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;(3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;(3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone;3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;(3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(3-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-{4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine;1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-3-morpholin-4-yl-propan-2-ol;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-diethylamino-ethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(1-methyl-piperidin-3-ylmethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-diisopropylamino-ethoxy)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(1-methyl-piperidin-4-yloxy)-phenyl]-pyridin-2-ylamine;N-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanesulfonamide;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-[4-(1,1-dioxo-1lambda*6*-isothiazolidin-2-yl)-phenyl]-pyridin-2-ylamine;N-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanesulfonamide;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-phenyl-pyridin-2-ylamine;N-(4-{6-amino-5-[(R)-1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanesulfonamide;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-thiophen-3-yl-pyridin-2-ylamine;5-benzo[b]thiophen-2-yl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;4-methyl-piperazine-1-carboxylic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea;1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-hydroxy-ethyl)-urea;1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea;(R)-3-amino-pyrrolidine-1-carboxylic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;(S)-3-amino-pyrrolidine-1-carboxylic acid(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;1-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(1-methyl-piperidin-4-yl)-urea;1-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(1-methyl-piperidin-4-yl)-urea;(R)-3-amino-pyrrolidine-1-carboxylic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;(S)-3-amino-pyrrolidine-1-carboxylic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;1-(4-(6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-hydroxy-ethyl)-urea;4-methyl-piperazine-1-carboxylic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;1-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-pyrrolidin-1-yl-ethyl)-urea;1-(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-3-(2-morpholin-4-yl-ethyl)-urea;(R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-amide;3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzamide;3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-amino-pyrrolidin-1-yl)-methanone;(3-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone;4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzoicacid;4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;N-[2-(4-acetyl-piperazin-1-yl)-ethyl]-4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-benzamide;4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-3-aminopyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-3-amino-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1yl)-methanone;(4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;(4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(1-methyl-piperidin-4-yl)-benzamide;4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(2-morpholin-4-yl-ethyl)-benzamide;4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-pyrrolidin-1-yl-propyl)-benzamide;4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-N-(3-morpholin-4-yl-propyl)-benzamide;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-pyrazol-4-yl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(2-diisopropylamino-ethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-pyridin-2-ylamine;{4-[6-amino-5-(3-fluoro-2-methoxy-benzyloxy)-pyridin-3-yl]-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(3-fluoro-2-methoxy-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;{4-[6-amino-5-(3-fluoro-2-isopropoxy-benzyloxy)-pyridin-3-yl]-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;5-(4-amino-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-aceticacid methyl ester;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-aceticacid;2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-1-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-ethanone;2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-1-((R)-3-hydroxy-pyrrolidin-1-yl)-ethanone;4-[2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-acetyl]-piperazine-1-carboxylicacid tert-butyl ester;2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenoxy)-1-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethanone;{4-[6-amino-5-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-pyridin-3-yl]-phenyl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;3-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-2-ylamine;N-{4-[6-amino-5-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide;3-(3-fluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yloxy)-5-(1H-pyrazol-4-yl)-pyridin-2-ylamine;3-[1-(2-chloro-3-fluoro-phenyl)-ethoxy]-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyridin-2-ylamine;5′-benzyloxy-[2,3′]bipyridinyl-6′-ylamine;5-benzyloxy-[3,3′]bipyridinyl-6-ylamine;3-benzyloxy-5-pyrimidin-5-yl-pyridin-2-ylamine;5-benzyloxy-[3,3′]bipyridinyl-6,6′-diamine;5′-(2-chloro-benzyloxy)-[2,3′]bipyridinyl-6′-ylamine;5-(2-chloro-benzyloxy)-[3,3′]bipyridinyl-6-ylamine;3-(2-chloro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine;5-(2-chloro-benzyloxy)-[3,3′]bipyridinyl-6,6′-diamine;5′-(4-chloro-benzyloxy)-[2,3′]bipyridinyl-6′-ylamine;5-(4-chloro-benzyloxy)-[3,3′]bipyridinyl-6-ylamine;3-(4-chloro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine;5-(4-chloro-benzyloxy)-[3,3′]bipyridinyl-6,6′-diamine;5′-(2-chloro-3,6-difluoro-benzyloxy)-[2,3′]bipyridinyl-6′-ylamine;5-(2-chloro-3,6-difluoro-benzyloxy)-[3,3′]bipyridinyl-6-ylamine;5-(2-chloro-3,6-difluoro-benzyloxy)-[3,4′]bipyridinyl-6-ylamine;3-(2-chloro3,6-difluoro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine;5-(2-chloro-3,6-difluoro-benzyloxy)-[3,3′]bipyridinyl-6,6′-diamine;5′-(2,6-dichloro-benzyloxy)-[2,3′]bipyridinyl-6′-ylamine;5-(2,6-dichloro-benzyloxy)-[3,3′]bipyridinyl-6-ylamine;5-(2,6-dichloro-benzyloxy)-[3,4′]bipyridinyl-6-ylamine;3-(2,6-dichloro-benzyloxy)-5-pyrimidin-5-yl-pyridin-2-ylamine;5-(2,6-dichloro-benzyloxy)-[3,3′]bipyridinyl-6,6′-diamine;5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6,6′-diamine;{6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-4-yl}-(4-methyl-piperazin-1-yl)-methanone;{6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-6-yl}-(4-methyl-piperazin-1-yl)-methanone;{6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-5-yl}-(4-methyl-piperazin-1-yl)-methanone;{6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-yl}-(4-methyl-piperazin-1-yl)-methanone;{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,4′]bipyridinyl-2′-yl}-(4-methyl-piperazin-1-yl)-methanone;5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6,6′-diamine;{6′-amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-5-yl}-(4-methyl-piperazin-1-yl)-methanone;{6′-amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-4-yl}-(4-methyl-piperazin-1-yl)-methanone;{6′-amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-6-yl}-(4-methyl-piperazin-1-yl)-methanone;{6′-amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-5-yl}-(4-methyl-piperazin-1-yl)-methanone;{6′-amino-5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-yl}-(4-methyl-piperazin-1-yl)-methanone;{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,4′]bipyridinyl-2′-yl}-(4-methyl-piperazin-1-yl)-methanone;5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-6′-ylamine;5′-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-6′-ylamine;5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ylamine;3-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-pyrimidin-5-yl-pyridin-2-ylamine;{6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[2,3′]bipyridinyl-5-yl}-(4-methyl-piperazin-1-yl)-methanone;5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-[3,4]bipyridinyl-6-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;5-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-fluoro-benzonitrile;4-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-piperidin-4-ol;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-piperidin-1-yl-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-pyrrolidin-1-yl-methanone;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-3-methyl-benzoicacid methyl ester;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(dimethyl-piperazin-1-ylmethyl)-phenyl]-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-3,5-dimethoxy-phenyl)-(dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-fluoro-phenyl)-(dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-3-fluoro-phenyl)-(dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-3-methyl-phenyl)-(dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-methyl-[1,4]diazepan-1-yl)-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-[1,4]diazepan-1-yl-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-piperazin-1-yl-methanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-vinyl-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,4S)-3,4-dihydroxy-pyrrolidin-1-yl)-methanone;5-[(1-benzyl-pyrrolidin-3-ylamino)-methyl]-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N-azetidin-3-yl-benzamide;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-N,N-dimethyl-benzenesulfonamide;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(6-methoxy-1H-benzoimidazol-2-yl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(6-methoxy-1-methyl-1H-benzoimidazol-2-yl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-(4-methyl-[1,4]diazepane-1-sulfonyl)-phenyl]-pyridin-2-ylamine;6-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-1-methyl-1H-indazole-3-carboxylicacid amide;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-methyl-1H-pyrazol-4-yl)-pyridin-2-ylamine;5-(3-chloro-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-fluoro-3-methyl-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-fluoro-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-trifluoromethoxy-phenyl)-pyridin-2-ylamine;5-benzo[1,3]dioxol-5-yl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenol;(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanol;3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzonitrile;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-methoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-dichloro-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,5-dimethyl-phenyl)-pyridin-2-ylamine;5-(5-chloro-2-methoxy-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;5-(3-chloro-4-fluoro-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(5-fluoro-2-methoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-isopropyl-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-dichloro-phenyl)-pyridin-2-ylamine;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzonitrile;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-difluoro-phenyl)-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-methanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-ethoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,5-dimethoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,4-dimethoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,6-dimethoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine;5-(2-chloro-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-trifluoromethoxy-phenyl)-pyridin-2-ylamine;1-(2-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-ethanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-fluoro-phenyl)-pyridin-2-ylamine;(2-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanol;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-o-tolyl-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2-methoxy-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,6-dimethyl-phenyl)-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-morpholin-4-yl-methanone;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-chloro-phenyl)-((3R,5S)-dimethyl-piperazin-1-yl)-methanone;4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-2-methyl-phenyl)-((3R,5S)-dimethyl-piperazin-1-yl)-methanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[4-((2R,6S)-2,6-dimethyl-morpholin-4-ylmethyl)-phenyl]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-morpholin-4-ylmethyl-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-dimethyl-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-m-tolyl-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-dimethoxy-phenyl)-pyridin-2-ylamine;5-biphenyl-3-yl-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;5-(3,5-bis-trifluoromethyl-phenyl)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,4-dichloro-phenyl)-pyridin-2-ylamine;1-(3-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-ethanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3,5-difluoro-phenyl)-pyridin-2-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(2,5-dichloro-phenyl)-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-4-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(3-ethoxy-phenyl)-pyridin-2-ylamine;(4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(3-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone;7-[4-(3,5-dimethyl-piperazine-1-carbonyl)-phenyl]-2-phenyl-4H-pyrido[3,2-b][1,4]oxazin-3-one;{4-[6-amino-5-(3-fluoro-2-trifluoromethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone;(4-[6-amino-5-(2,6-difluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone;[4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenyl]-(3,5-dimethyl-piperazin-1-yl)-methanone;(4-{6-amino-5-[1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-ethyl-piperazin-1-yl)-methanone;[4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenyl]-(4-ethyl-piperazin-1-yl)-methanone;{4-[6-amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone;3-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzoicacid methyl ester;3-{2-amino-5-[4-(3,5-dimethyl-piperazine-1-carbonyl)-phenyl]-pyridin-3-yloxymethyl}-benzoicacid methyl ester;(4-[6-amino-5-(2-methyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;[4-(6-amino-5-cyclohexylmethoxy-pyridin-3-yl)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;4-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-[2-(3-hydroxy-phenyl)-ethyl]-benzamide;4-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-[2-(2,6-dichloro-phenyl)-ethyl]-benzamide;4-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-(1-benzyl-piperidin-4-yl)-benzamide;4-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide;(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-ethyl-piperazin-1-yl)-methanone;{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone;(6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanone;5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-6′-(2-morpholin-4-yl-ethoxy)-[3,3′]bipyridinyl-6-ylamine;6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-1-(2-pyrrolidin-1-yl-ethyl)-1H-[3,3′]bipyridinyl-6-one;5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-6′-(2-pyrrolidin-1-yl-ethoxy)-[3,3′]bipyridinyl-6-ylamine;6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-[3,3′]bipyridinyl-6-one;(4-{6-amino-5-[1-(2,4,6-trimethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;(4-{6-amino-5-[1-(2-chloro-6-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-fluoro-phenyl)-pyridin-2-ylamine;6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-1H-[3,3′]bipyridinyl-6-one;5′-bromo-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4-dimethylamino-phenyl)-pyridin-2-ylamine;5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-2′-methoxy-[3,3′]bipyridinyl-6-ylamine;3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-indol-5-yl)-pyridin-2-ylamine;(4-{6-amino-5-[1-(2,6-dichloro-phenyl)-propoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone;[4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenyl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;3-(2,6-dichloro-3-fluoro-benzyloxy)-5-thiazol-2-yl-pyridin-2-ylamine;(4-{6-amino-5-[1-(2-fluoro-6-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;3-(2,6-dichloro-3-fluoro-benzyloxy)-5-(1-methyl-1H-imidazol-2-yl)-pyridin-2-ylamine;{4-[6-amino-5-(2,4,6-trimethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;{4-[6-amino-5-(2,3,5,6-tetramethyl-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;{4-[6-amino-5-(2,4,6-trifluoro-benzyloxy)-pyridin-3-yl]-phenyl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;(4-{6-amino-5-[1-(2-fluoro-6-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-N-methyl-nicotinamidine;6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-N-(2-morpholin-4-yl-ethyl)-nicotinamidine;(4-{6-amino-5-[1-(2,4,5-trifluoro-phenyl)-propoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;(4-{6-amino-5-[1-(6-chloro-2-fluoro-3-methyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;3-(1-{2-amino-5-[4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-pyridin-3-yloxy}-ethyl)-benzoicacid; and pharmaceutically acceptable salts, and hydrates thereof.